Year 4 Module C

Medicine
Hematology
Done by
Elaf BaharethaHatimialmagrabi
TABLE OF CONTENTS
Anemia .............................................................. 3 Thrombotic Thrombocytopenic Purpura (TTP) .... 30
Iron deficiency anemia (IDA) .......................................5 Hemolytic Uremic Syndrome (HUS) ..................... 31
Anemia of chronic disease ..........................................6 Disseminated Intravascular Coagulation (DIC) .... 33
Vitamin B12 deficiency anemia...................................7 Bleeding Diathesis ............................................ 34
Folate deficiency anemia ............................................8 Hemophilia ............................................................... 34
Sideroblastic anemia ...................................................8 Von Willebrand disease ........................................... 38
Aplastic anemia - pancytopenia ..................................9 High Blood Count ............................................. 41
Rare causes of anemia ..............................................10 Leukocytosis ............................................................. 41
Hemolytic anemia ............................................ 11 Thrombocytosis ........................................................ 41
Hemolytic anemia causes .........................................12 Erythrocytosis .......................................................... 42
Coombs testing .........................................................15 polycythemia rubra vera .......................................... 42
Important diseases related to hemolytic anemia .....16 Essential thrombocythemia (ET) .............................. 43
Glucose-6-phosphate dehydrogenase deficiency Acute leukemia ........................................................ 44
(Favism) ..................................................................... 16
Chronic leukemia ..................................................... 46
Autoimmune hemolytic anemia (AIHA)............... 16 Leukostasis ............................................................... 47
Hereditary spherocytosis ..................................... 17
Transfusion medicine ....................................... 48
Hemoglobinopathies ........................................ 18 Transfusion reactions .............................................54
Sickle cell ...................................................................18
Coagulation ..................................................... 57
Thalassemia ..............................................................21
Heparin-Induced Thrombocytopenia (HIT) .............. 59
Thrombocytopenia ........................................... 25 Additional Topics in hematology .............................. 60
Immune Thrombocytopenic Purpura (ITP) ...............26
Hypercoagulable states (Thrombophilia) ............ 60
Microangiopathic Hemolytic Anemia (MAHA) ..........30
Antiphospholipid syndrome ................................ 61
Anemia
Sources: AMBOSS, OnlineMedEd, Step-up to Medicine, The slides.

Objectives
Knowledge Cognitive Skills
1. Identify the major causes of iron deficiency, B12 and 1. Choose the most appropriate investigations to diagnose
folate deficiency different types of anemia (blood and bone marrow)
2. Recognize the rare causes of anemia (multiple 2. Interpret blood tests (complete blood count CBC,
myeloma, myelofibrosis) differential count, peripheral blood film, red cell indices,
ferritin, serum iron profile, vitamin B12, Folate, direct
antiglobulin test (DAT), methylmalonic acid, homocysteine,
and serum protein electrophoresis)
3. Identify red flags symptoms and signs that require further 3. Formulate and prioritize a differential diagnosis for
investigations (e.g., anti-transglutaminase antibodies Anti anemia, and
TTG Ab, or Colonoscopy)
4. Construct a diagnostic approach to different types of
anemia
5. Develop an evidence-based management plan for iron
deficiency anemia, B12 or Folate deficiency
6. Appropriately prioritize referral to Hematology Clinic
7. Demonstrate the appropriate skills for patient education

Definition
A low oxygen carrying capacity condition due to decrease in hemoglobin concentration or dysfunctional RBC
In a different definition: a decrease in the absolute number of circulating RBCs as measured by hemoglobin or
hematocrit

WHO criteria for anemia:

Men: Hb<13.5 g/dL
Women: Hb<12 g/dL

As a general rule in anemia: Blood transfusion is not recommended unless either of the following is true:
The Hb concentration <7 g/dL
The patient requires increased oxygen-carrying capacity (e.g., patient with coronary artery disease or some other
cardiopulmonary disease)

Clinical features (these anemic manifestations are the same all patients of anemia, regardless of the cause)
Exertional dyspnea, fatigue, headache
Palpitations/Tachycardia
Bounding pulses and flow murmur (systolic murmur)
Pallor (e.g., on mucous membranes, conjunctivae)
Severe anemia can lead to cardiac ischemia if the oxygen demand of the myocardium is not met (e.g., demand
ischemia)
Possibly heart failure (anemia-induced heart failure)
Pica (craving for ice or dirt)
Features of extramedullary hematopoiesis may be present in certain severe, chronic forms of anemia (e.g.,
thalassemia, myelofibrosis).
Signs/symptoms of underlying cause
o Orthostatic lightheadedness
o Syncope
o Hypotension if acute bleeding
o Jaundice (in hemolytic anemia)
o Blood in stool if GI bleeding
Approach to diagnosing anemia
The first test to order is a CBC:
1. Low Hemoglobin and Hematocrit will confirm diagnosis of anemia
2. MCV is the initial test for patients with anemia, classifies anemia into:
a. Microcytic anemia: mostly caused by impaired production
b. Macrocytic anemia: mostly caused by impaired production
c. Normocytic anemia: mostly caused by destruction

Microcytic Normocytic Macrocytic

MCV <80 fl 80-95 fl >95 fl

MCH <27 pg >27 ph High/N

MCHC <32% N N

Mechanism Insufficient hemoglobin Decreased blood volume and/or Insufficient nucleus maturation relative to
production decreased erythropoiesis cytoplasm expansion due to
Defective DNA synthesis
Defective DNA repair

E.g. Iron deficiency anemia Hemolytic anemia Megaloblastic anemia

Thalassemia Acute blood loss o Vit B12 deficiency
Sideroblastic bone marrow failure o Folic acid deficiency
Anemia of chronic disease Anemia of chronic kidney disease Non-Megaloblastic anemia
Lead poisoning Sickle cell anemia
Aplastic anemia

Note: the picture is important and gives an overview of the following:

Microcytic anemia (MCV<80 fL)

Iron studies: initial investigation for microcytic anemia
o Low Ferritin OR normal/high ferritin and high Total iron binding capacity (TIBC): iron deficiency anemia
Important note: TIBC measures the blood's ability to attach itself to iron. High TIBC means that iron
levels are low: there isn't much iron to attach to, and a lot of free transferrin in the blood
o Normal/high ferritin and low TIBC: anemia of chronic disease
o Serum iron levels are decreased in iron deficiency anemia and anemia of chronic disease
Peripheral blood smear, reticulocyte count, RDW: not routinely done for microcytic anemia because findings are
often nonspecific
 o Low reticulocyte count (<2%): iron deficiency anemia, thalassemia trait, anemia of chronic disease,
sideroblastic anemia, and lead poisoning
Iron deficiency anemia and thalassemia trait are the most common cause of microcytic anemia
Basophilic stippling on peripheral blood smear suggests lead poisoning or sideroblastic anemia. Ringed
sideroblasts are not usually seen with iron deficiency anemia, but seen with sideroblastic anemia
o High reticulocyte count (>2%): thalassemia

Macrocytic anemia (MCV>100 fL)

Peripheral blood smear (PBS): initial investigation for macrocytic anemia to look for megaloblastic change:
Megaloblastic anemia: Hypersegmented neutrophils (>5 lobes, look at pictures below): caused by vitamin B12
and Folate deficiency
o Serum homocysteine and methylmalonic acid levels: for patients with borderline serum vitamin B12 and/or
folate levels
Normal methylmalonic acid: folic acid deficiency
High methylmalonic acid: vitamin B12 deficiency
Serum homocysteine is elevated in both (more in folic acid deficiency)
Non megaloblastic anemia: No hypersegmented neutrophils: caused by liver cirrhosis, alcohol abuse,
methotrexate, hypothyroidism, and Myelodysplastic syndrome
o consider Electrophoresis if reticulocyte count and metabolic panels are normal and there is no history of
drug/alcohol use
High HbF level indicates Diamond-Blackfan anemia

Normal Hypersegmented

Note: another way to differentiate megaloblastic from non megaloblastic anemia, is by the MCV: if the MCV is higher

Normocytic anemia (MCV 80 100 fL)

Reticulocyte index: in all patients with normocytic anemia to evaluate bone marrow response
o low reticulocyte index (<2%) indicates ineffective or decreased RBC production
o high reticulocyte index (>2%) indicates high destruction of RBC
Additional diagnostics:
o Peripheral blood smear
o Bone marrow biopsy: Prussian blue staining if sideroblastic anemia is suspected

Iron deficiency anemia (IDA)

The most common cause of anemia worldwide

Causes
1. Chronic
a. Most common cause of iron deficiency anemia in adults
b. Menstrual blood loss is the most common cause in young female patients
c. Gastrointestinal blood loss (e.g., colon cancer, ulcerative colitis) is the most cause in male and
postmenopausal women
2. Dietary deficiency/increased iron requirements primarily seen in these three age groups:
a. Infants and toddlers: occurs especially if the diet is predominantly human milk (low in iron). Children in this
age group also have an increased requirement for iron because of accelerated growth. It is most common
between 6 months and 3 years of age
b. Adolescents: increased iron requirement for rapid growth and loss of menstrual blood
c. Pregnant women: increased iron requirement

Clinical features
1. Pallor
2. Fatigue, generalized weakness
3. Dyspnea on exertion
4. Orthostatic lightheadedness
5. Hypotension, if acute
6. Tachycardia

Diagnosis
1. Laboratory tests
a. Decreased serum ferritin most reliable test available
b. Increased TIBC/transferrin levels
c. Low TIBC saturation
d. Decreased serum iron
e. Microcytic, hypochromic RBCs on peripheral smear
2. Bone marrow biopsy: the gold standard, but rarely performed. Indicated if laboratory evidence of iron deficiency
anemia is present and no source of blood loss is found
3. If GI bleeding is suspected: Colonoscopy is done, to rule out colon cancer, especially in elderly patients
4. Menstruating women may be started on iron replacement with no further investigation of an underlying cause.
But always investigate men and postmenopausal women

Treatment
1. Oral iron replacement (ferrous sulfate: 200mg 3 times daily for 3-6 months)
2. Parenteral iron replacement
a. Iron dextran can be administered IV or IM
b. This is rarely necessary because most patients respond to oral iron therapy. It may be useful in patients with
poor absorption, patients who require more iron than oral therapy can provide, or patients who cannot
tolerate oral ferrous sulfate
3. Blood transfusion is not recommended unless anemia is severe or the patient has cardiopulmonary disease

Note:
Folic acid supplement is necessary in pregnancy to prevent neural tube defect
Iron supplement is necessary in pregnancy to prevent microcytic anemia
o Iron deficiency anemia is the most common anemia in pregnancy

Anemia of chronic disease

Anemia due to continuous inflammation by chronic disease due to impaired iron metabolism and it is the second
most common anemia (after iron deficiency anemia)

Etiology
chronic renal failure (this is the most common cause of anemia of
chronic disease)
Inflammation (e.g., rheumatoid arthritis, systemic lupus erythematosus)
Malignancy (e.g., lung cancer, breast cancer, lymphoma, Hodgkin disease)
o (excluding malignant disease in which blood loss is a major factor as in colon cancer)
Chronic infections (e.g., tuberculosis, lung abscess)
Anemia as a result of endocrine failure (Diabetes mellitus)
Anemia of hepatic disease
Diagnostics
Low serum iron, iron saturation, total iron binding capacity (TIBC) and reticulocyte count
High serum ferritin (unlike iron deficiency anemia)
Peripheral blood smear can reveal normocytic and normochromic anemia but may be microcytic and
hypochromic as well

Treatment
Treat the underlying cause
Blood transfusion if required
EPO (Erythropoietin) injections in chronic incurable diseases (e.g., chronic kidney disease or cancer)

Vitamin B12 deficiency anemia

General features
1. Vitamin B12 is involved in two important reactions:
a. As a cofactor in conversion of homocysteine to methionine
b. As a cofactor in conversion of methylmalonyl CoA to succinyl CoA
2. Vitamin B12 stores in the liver are plentiful and can sustain an individual for 3 or more years
3. The main dietary sources of vitamin B12 are meat and fish
4. Vitamin B12 is bound to intrinsic factor (produced by gastric parietal cells), to be absorbed by the terminal ileum

Causes
Malabsorption
o Low intrinsic factor (also called Pernicious anemia)
Atrophic gastritis due to autoimmunity and infections
Gastrectomy
o Reduced uptake
Alcohol use disorder
Crohn disease, celiac disease
Pancreatic insufficiency
Surgical resection of the ileum
Malnutrition
o Psychiatric: anorexia nervosa
o Strict vegan diets (occurs after years)
Increased demand e.g., during pregnancy, breastfeeding, fish tapeworm (Diphyllobothrium latum) infection, and
leukemia

Clinical features
Signs and symptoms of anemia
Neurological disturbances that are generally symmetrical, in untreated B12 deficiency, irreversible neurologic
disease can result
o Peripheral neuropathy: tingling, numbness, pins-and-needles sensation, coldness (especially in the lower
extremities)
o Subacute combined degeneration of spinal cord: symmetrical demyelination of the spinal cord tracts
o Autonomic dysfunction: impotence and incontinence
Neuropsychiatric disease (e.g., reversible dementia, depression, paranoia)
Worsening vision

Diagnosis
Hematological findings:
Signs of megaloblastic anemia, seen on CBC and peripheral blood film
o
o Hypersegmented neutrophils, low Reticulocytes
Frequently thrombocytopenia and leukopenia (possibly pancytopenia)
Approach
If vitamin B12 serum levels are decreased (<100 pg/mL), determine the underlying cause
o Antibodies against intrinsic factors and against gastric parietal cells. If negative:
o Schilling test, also known as a Vitamin B12 absorption test (not routinely done, patients is given B12 and
urine is monitored)
If vitamin B12 serum levels are normal:
o Measure homocysteine: elevated in both vitamin B12 deficiency and folate deficiency
o Measure methylmalonic acid (MMA) to help rule out folate deficiency (MMA is normal in folate deficiency
and elevated in vitamin B12 deficiency)

Treatment
Oral replacement, if oral intake is not tolerated, malabsorption disease, or severe neurological symptoms are
present, we use IM replacement
Note: In clinical practice, most doctors have IM replacement as their first choice

Folate deficiency anemia

General features
1. Folic acid (vitamin B9) stores are limited. Inadequate intake of folate over a 3-month period can lead to
deficiency
2. Green vegetables are the main source of folate. Overcooking vegetables can remove folate.

Causes
Malnutrition Increased requirement
o Insufficient intake, malnutrition o Pregnancy/lactation
o Chronic alcohol use o Severe hemolytic anemia
Malabsorption Drug-related
o Small bowel disease o Antiepileptic drugs (e.g., phenytoin)
o Surgical resection of the small intestine o Sulfonamides
o Trimethoprim
Clinical presentation
Signs and symptoms of anemia
Maternal deficiency: fetal spina bifida/anencephaly
Unlike vitamin B12 deficiency, folate deficiency does not result in neurological symptoms

Diagnosis
Serum folate levels may be low but are difficult to interpret
Low red cell folate levels indicate prolonged folate deficiency and are probably the most relevant measure
Corroborative findings: Macrocytic dysplastic blood picture, Megaloblastic marrow

Treatment
Oral folic acid 5 mg daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance
therapy. Prophylactic folic acid in pregnancy prevents megaloblastosis in women at risk, and reduces the risk of fetal
neural tube defects

Sideroblastic anemia
Anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria

Etiology
Inherited: X-linked -ALA-synthase gene defect
o -aminolevulinic acid is the first compound in the heme/porphyrin synthesis pathway.
Acquired
o Alcohol use disorder
o Lead poisoning
o
o Myelodysplastic syndrome
Diagnosis
CBC: microcytic anemia
Serum iron studies will show:
o High ferritin, iron

o Normal/low TIBC
Peripheral blood smear
o Basophilic stippling of RBCs
o Prussian blue staining of bone marrow: ringed sideroblasts
Basophilic stippling on peripheral blood smear suggests lead poisoning or sideroblastic anemia. Because
ringed sideroblasts are not usually seen in lead poisoning, they can help to distinguish between this
condition and sideroblastic anemia.

Treatment
Cessation of the offending agent
-ALA synthase)

Aplastic anemia - pancytopenia

Bone marrow failure leading to pancytopenia (anemia, neutropenia, thrombocytopenia)

Causes
Idiopathic (majority of cases)
Radiation exposure
Medications (e.g., chloramphenicol, sulfonamides, gold, carbamazepine)
Viral infection (e.g., human parvovirus, hepatitis C, Epstein-Barr virus, cytomegalovirus, herpes zoster, varicella,
HIV)
Chemical exposure (e.g., benzene, insecticides)
Patients with paroxysmal nocturnal hemoglobinuria
o Lab findings show hemolysis
o Morning dark urine
o Pancytopenia
o Multiple thrombus in veins

Important note:
Consider endoscopy and/or colonoscopy in patients with anemia and positive FOBT (Fecal occult blood test)
o IDA in middle age or elderly male is secondary to gastrointestinal malignant neoplasm (Carcinoma of the
colon or rectum should be ruled out)
Imaging is not routinely indicated for the workup of anemia unless bleeding is suspected.
Consider abdominal ultrasound to evaluate for hypersplenism, liver disease, or renal disease.
Consider CT and/or PET scan if malignancy is suspected.
o Note: Lymphoma will produce normochromic, normocytic anemia

Important note about Celiac disease (Gluten-sensitive enteropathy)

It is an autoimmune disorder characterized by an intestinal hypersensitivity to gluten (a grain protein)
They will have extraintestinal symptoms such as:
o Malabsorption symptoms: fatigue, weight loss, vitamin deficiency, iron deficiency anemia
Common indication for testing includes:
o Iron deficiency anemia unresponsive to treatment
In adult patients with celiac disease, iron deficiency anemia is very common and affects about a third of
newly diagnosed patients.
That is why we do IgA tissue transglutaminase antibody (tTG IgA) as an initial test
Rare causes of anemia
Multiple myeloma
It is a malignant plasma cell dyscrasia characterized by uncontrolled proliferation and the diffuse infiltration of
monoclonal plasma cells in the bone marrow, diagnostic includes:
Serum protein electrophoresis or free light chain assay (best initial test)
Bone marrow biopsy (confirmatory test)
Laboratory tests (CBC and biochemistry) to assess for hypercalcemia, anemia and renal insufficiency
o CBC will show anemia, thrombocytopenia, leukopenia and eventually pancytopenia
Imaging to assess for bone lesions
Important note: CRAB indicates organ damage: Calcium increased, Renal insufficiency, Anemia, and Bone lesions

Myelofibrosis
It leads to bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly, patient will present with:
Constitutional symptoms, Anemia, Symptomatic splenomegaly, Thromboembolic events, Petechial bleeding and
Increased infections
Diagnostics
Classic presentation: anemia, thrombocytosis, and leukocytosis
o Thrombocytopenia (secondary to massive splenomegaly)
o Pancytopenia (secondary to severe marrow fibrosis)
In myelofibrosis, RBCs shed tears (teardrop cells) because they have been forced out of the fibrosed bone
marrow (extramedullary hematopoiesis).

Important note: Pancytopenia

Definition: a decrease in the number of cells of all cell lines (i.e., RBCs, WBCs, and platelets) in the peripheral blood
Causes
Aplastic anemia
Multiple myelomas
Myelodysplastic syndrome
Acute and chronic leukemia
Chemotherapy
Autoimmune disease (e.g., SLE)
Infections (e.g., CMV, EBV)
Hemolytic anemia
Sources: AMBOSS, OnlineMedEd, Step-up to Medicine, The slides.

Objectives
Knowledge Cognitive Skills
1. Describe hemolysis and hemolytic anemias (HA) and their 1. Choose the most appropriate investigations to diagnose
causes, classifications (intravascular and extravascular hemolysis hemolytic anemia (blood tests) based on the available clinical
and differentiate between them) data
2. Describe direct antiglobulin test (DAT) and antibody screening 2. Interpret blood tests (CBC with differential, peripheral blood
tests film, coagulation profile, fibrinogen, hemolytic work up, Direct
antiglobulin test DAT)
3. List causes and management of warm and cold autoimmune 3. Formulate and prioritize a differential diagnosis for hemolytic
hemolytic anemia anemia, with an approach to warm and cold autoimmune
hemolytic anemia
5. Develop an evidence-based management plan for hemolytic
anemias

Definition: Hemolytic anemias are characterized by an excessive breakdown of premature red blood cells (RBCs).
They can be classified according to the cause of hemolysis (intrinsic or extrinsic) and by the location of hemolysis
(intravascular or extravascular)

Severity of hemolysis depends on:

The onset/rate of RBC destruction
Marrow capacity to increase erythroid production

Types of hemolytic anemia:

By location of RBC breakdown

Type Definition Causes

Intravascular Increased destruction of RBCs within the blood

hemolytic anemia vessels G6PD deficiency
Antibody-
Complement-mediated hemolysis

Extravascular Increased destruction of RBCs by the RBC defects

hemolytic anemia reticuloendothelial system (primarily the Antibody-mediated hemolysis (warm and cold
spleen, liver), commonly causes splenomegaly agglutinin disease)

By RBC pathology

Type Definition Causes

Increased destruction of RBCs due to a defect RBC membrane defects

Intrinsic hemolytic
within the RBC Enzyme defects
anemia
Note: they are often inherited. Hemoglobinopathies

Mechanical destruction in large and small vessels

Abnormal breakdown of normal RBCs Autoimmune reactions
Extrinsic hemolytic Infections
anemia The RBCs themselves are not defective but may Hypersplenism
become damaged. Alloimmune reactions
Tumors (e.g., chronic lymphocytic leukemia)
General pathophysiology

creased levels of oxygen to tissues.

In hemolytic anemia: Laboratory blood changes can happen due to destruction of premature RBCs such as:
Increase in lactate dehydrogenase levels (enzyme which is found in RBCs)
Normally RBCs contain hemoglobin molecules, and when they are being broken down, you will get:
Increased in globin levels which will be recycled
Increased in heme levels which will break down more causing increased in Iron levels + unconjugated
bilirubin

and not being fully cleared by the body, it will carry it to the reticulo-endothelial system to properly remove
those free hemoglobin molecules
This will cause decrease level of haptoglobin
Increase in the reticulocyte count

Hemolytic anemia causes

Intravascular hemolysis causes
tion of erythrocytes (e.g., from mechanical heart

Microangiopathic anemia (e.g., thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,

disseminated intravascular coagulation and systemic lupus erythematosus)
RBCs can get destroyed because as they passed through a formed clot, their cell membrane can get
damaged causing their death
In Microangiopathic hemolysis: you can find fragmented RBCs in patients urine
-mediated
hemoglobinuria, paroxysmal nocturnal hemoglobinuria)
Destruction of RBCs through complement activation
-
Antibodies recognize antigens on RBCs at temperature below normal core body temperature and they
induce RBCs destruction
They can be a type of extravascular hemolytic anemia as well due to IgM
Giving IV fluids will cause osmotic lysis following an infusion of hypotonic solutions
RBCs will swell up taking the water then burst
-mediated hemolysis (transfusion ABO incompatibility and hemolytic

Important note: -
extravascular hemolysis.
Hemosiderin urine: A brown urine typically because of iron from the heme that appears 3 to 4 days after the
onset of the hemolytic conditions

Note of definition:
which hemolysis is
mediated by monoclonal cold-
Warm agglutinin hemolytic anemia: an autoimmune disease characterized by the binding of heat-sensitive
ion of RBCs in the reticuloendothelial
system
Extravascular hemolysis causes
Extracorpuscular causes due to problems not within the RBCs itself

body temperature
Antibody binds into the cell membrane of RBC bringing them to phagocytes promoting its clearance
Hypersplenism due to sequestration of the cells and an increase in the activity of the monocytes and
macrophage
Infections causing increased destruction of RBCs (e.g., Babesia, malaria, Bartonella bacilliformis)
Intracorpuscular which is a problem inside the RBCs such as the enzymes and morphology
Usually, congenital

Such as: sickle cell anemia, thalassemia

Cell membrane defect such as:
Hereditary spherocytosis: An autosomal dominant disease caused by red blood cell membrane protein
defects, which render the red blood cells more vulnerable to osmotic stress and hemolysis.
RBC morphology: Small, spherical, no central pallor
Hereditary el
RBC morphology: Oval or elliptical
Hereditary stomatocytosis
Enzyme deficiencies
Such as: Glucose-6-

Remember
RBC membrane defects
Paroxysmal nocturnal hemoglobinuria (PNH)
Hereditary spherocytosis
Hereditary elliptocytosis
Enzyme defects
Pyruvate kinase deficiency
Glucose-6-phosphate dehydrogenase deficiency
Hemoglobinopathies
Hemoglobin C disease
Sickle cell disease
Thalassemia

Clinical features of Hemolytic anemia patients:

Signs of anemia
New onset of pallor
Fatigue
Exertional dyspnea
In severe cases: tachycardia, angina pectoris, leg ulcers (due to poor blood flow)
Signs of hemolysis
Jaundice
Pigmented gallstone (due to accumulation of indirect bilirubin in the bile)
Splenomegaly (in the case of extravascular hemolysis)
Back pain and dark urine in severe hemolysis with hemoglobinuria
Hemoglobin is nephrotoxic.
In case of intravascular hemolysis
Symptoms and signs of possible underlying systemic illness (autoimmune disease, malignancy)
Diagnostic of hemolytic anemia
Perform initial laboratory studies to confirm anemia and hemolysis and classify anemia by morphology.
1. Anemia workup: CBC with MCV, reticulocyte count
2. Hemolysis workup: Add LDH, haptoglobin, bilirubin, urinalysis, and peripheral blood smear (PBS)
Obtain a direct Coombs test (i.e., DAT) to narrow the differential:
1. DAT positive: antibody-mediated hemolytic anemia
2. DAT negative: non-antibody-mediated hemolytic anemia
Important ( ): A test used to determine if hemolysis is
immune-mediated. Patient RBCs are washed and incubated with anti-human antibodies. A positive test (indicated by

What to see in the laboratory studies

Normocytosis: typical finding for most hemolytic anemias

reticulocytosis; consider other causes of macrocytosis (e.g., megaloblastic
anemia)
Microcytosis: consider thalassemia and/or iron deficiency
WBC count: can be elevated due to inflammation or malignancy
Platelets: decreased in MAHA and in Evan syndrome
Evan syndrome: A condition in which two or more hematologic immune cytopenias are present at the same
time, most commonly ITP and AIHA
Reticulocyte count: Use the corrected reticulocyte count for patients with anemia.

Iron studies are usually normal in hemolytic anemia, however, iron deficiency can be seen in chronic
intravascular hemolysis
Elevated lactate dehydrogenase (LDH)
Elevated indirect bilirubin
Decreased haptoglobin
Urinalysis abnormalities
Hemoglobinuria: Presence of free hemoglobin in urine. A common cause is intravascular hemolysis (e.g.,
transfusion mismatch).
Hemosiderin Uria
Urobilinogen: A breakdown product of bilirubin
Peripheral blood smear abnormalities

Immature red blood cell that develops in the bone marrow during erythropoiesis.

Seen in DIC, TTP/HUS, HELLP syndrome and mechanical heart valves.

spherocytes
Seen in immunologically mediated hemolytic anemias and hereditary spherocytosis.

Heinz bodies and bite cells in G6PD deficiency

 Finding in intra/extravascular hemolysis
Description Intravascular hemolysis Extravascular hemolysis

Seen in marked
Urine hemosiderin ++ Negative
intravascular hemolysis

Urine hemoglobin Brown-colored urine ++ Negative

Occurs in extravascular
Urobilinogen Usually absent Present
hemolysis

Lactate
More prominent in Elevated Elevated
dehydrogenase
intravascular hemolysis +++ ++
(LDH)

Indirect bilirubin indirect bilirubin ++ +++

More prominent in
extravascular hemolysis

Spherocytes in hereditary spherocytosis and

Heinz bodies and bite cells
immune-mediated hemolysis (e.g., warm
in G6PD deficiency
AIHA, hemolytic transfusion reactions)
Schistocytes in MicroAHA
RBC agglutination in cold agglutinin disease
Detect abnormal RBC and Macroangiopathic
Peripheral smear (CAD)
forms hemolytic anemia
Sickle cells in sickle cell disease
Intracellular organisms
Target cells in sickle cell disease, thalassemia
(e.g., in malaria,
Teardrop cells in thalassemia
babesiosis, bartonellosis)
Smudge cells (Gumprecht shadows) in chronic
lymphocytic leukemia (CLL)

Coombs testing (Antiglobulin testing)

Description: A special reagent is added to patients' blood samples: Coombs serum, which contains anti-human
globulins (AHGs) that detect and adhere (with 2 binding sites) to immune proteins that mediate hemolysis, (i.e.,

RBC agglutination is considered a positive result, absence of RBC agglutination is considered a negative result
Types (Direct and indirect):

Direct Coombs test (DAT) Indirect Coombs test

detection of anti-RBC antibodies in the serum using a panel of RBC with

Detection of antibodies and/or complement proteins on the
known surface antigen.
surface of RBCs (normally neither found on RBC surface).
Transfusion medicine (workup and prevention of transfusion reactions)
Workup of hemolytic anemia
Perinatal care (workup and prevention of HDFN)

complement are on surface, coombs reagent will link the cell antigens then add coombs' reagent to the mixture. If anti-RBC antigens are
together and causes RBC agglutination in the serum, agglutination will occur

Indications:
Blood typing
Positive result indicates:
Screening for Rh-negative mothers
Autoimmune hemolytic anemia (warm AIHA or cold AIHA)
Alloimmune hemolytic anemia Patients with suspected transfusion reactions
Transfusion reaction Newborns with signs of hemolysis (HDFN)
Positive result
Negative result: Suggests non-antibody-mediated hemolysis,
Indicates the presence of freely circulating anti-RBC antibodies present
such as Microangiopathic hemolytic anemia (MAHA)
in the patient's serum that may be responsible for HDFN or transfusion
reactions.
 Important diseases related to hemolytic anemia
Glucose-6-phosphate dehydrogenase deficiency (Favism)
An impaired regeneration of reduced glutathione, an important antioxidant, which makes RBCs more susceptible to
oxidative stress and can result in episodic hemolytic anemia with exposure to oxidative conditions.
Condition is inherited in an X-linked recessive
Affects primarily males of African, Mediterranean and Asian descent
Usually asymptomatic, but a sudden surge in oxidative stress (e.g., after infection, consumption of fava beans, or
various drugs) may lead to a life-threatening hemolytic crisis.

G6PD assay will reveal deficient NADPH formation

Clinical features
Arise within 2 3 days after increased oxidative stress
Sudden onset of back or abdominal pain
Sudden anemia
Jaundice
Dark urine; Due to hematuria/hemoglobinuria
Transient splenomegaly
Treatment is supportive and avoids triggers!
ALWAYS remember: G6PD protects RBC against oxidative damage

Autoimmune hemolytic anemia (AIHA)

Are a collection of disorders characterized by the destruction of RBCs through antibody-mediated hemolysis
(extravascular and/or intravascular). Associated with either lymphoproliferative disease or collagen vascular disease
There are two broad types, categorized by the temperature at which the antigen-antibody reactions maximally
occur: cold agglutinin hemolytic anemia (cold AIHA) and warm agglutinin hemolytic anemia (warm AIHA)

Warm AIHA Cold AIHA

Cold-sensitive antibodies (cold agglutinins): mostly IgM antibodies cause

Heat-sensitive antibodies: Mostly polyclonal IgG antibodies that first extravascular hemolysis and acute intravascular hemolysis
bind to multiple RBC antigens Intravascular hemolysis can occur, mediated through the complement
system, which is activated by IgM antibodies bound to RBCs.

The antigen-antibody reaction is triggered by body temperature of The antigen-antibody reaction is triggered by low body temperature
and/or cold ambient temperatures.

Mostly idiopathic
Idiopathic
Secondary causes (Acute or Chronic)
Secondary to other diseases, including:
Malignancy (predominantly B-cell lymphoma, chronic
Mycoplasma pneumoniae or EBV infection (Mononucleosis) or
lymphocytic leukemia)
CMV
Autoimmune diseases (e.g., SLE or RA)
Malignancy (e.g., non-Hodgkin lymphoma, CLL)
Certain drugs (e.g., penicillin -methyldopa)

Direct coombs test (DAT): positive for C3d

DAT positive for IgG
PBS: abundant spherocytes The optimal temperature for the antigen-antibody reaction is 0-4°C.
PBS: agglutination of RBCs; spherocytes may be seen

Advise all patients to avoid exposure to the cold and keep them
Acute therapy
warm.
Indications: Severe symptoms of anemia or Hb < 6 7 mg/dL
Transfuse in blood warmer if needed.
Early treatment with high-dose glucocorticoids (Prednisone)
First-line treatment: rituximab (anti-CD20 antibody) on the long-
Second-line: rituximab
term therapy
Rescue therapy with IVIG or plasma exchange
Splenectomy is not recommended for cold AIHA, It is not effective as
Third line: steroid-sparing immunosuppressants or splenectomy
most extravascular hemolysis occurs in the liver.
RBC transfusion if needed after steroids but be careful!
Poor response to steroid
Remember
Warm weather is G Warm AIHA is IgG mediated.
Cold weather is MMMMiserable: Cold (IgM) AIHA is seen in Malignancy (CLL), Mycoplasma pneumonia, and
Mononucleosis.
Spherocytes may be seen in both cold AIHA and warm AIHA. However, abundant spherocytosis is characteristic
of warm AIHA.

Hereditary spherocytosis
It is an autosomal dominant disease that is caused by red blood cell (RBC) membrane protein defects, which render
the RBCs more vulnerable to osmotic stress and hemolysis.

Etiology: Family history often positive for relatives who required splenectomy and/or developed cholelithiasis at a
young age

Clinical features
Onset of symptoms in infancy or childhood, but some severe cases can start at newborns or even in utero
(hydrops fetalis)
Anemia (severe during second or third week of life) and pallor

Splenomegaly with left upper quadrant pain

Black pigment gallstones (made of calcium bilirubinate), may lead to cholecystitis

Diagnostic
Normocytic anemia but Increased mean corpuscular hemoglobin concentration decrease in RBC cell
volume (caused by a decrease in RBC water content), whereas the hemoglobin content remains constant
Findings of hemolytic anemia
Negative Coombs test; unlike autoimmune hemolytic anemia which is positive in theirs
Characteristic spherocytes (small round cells without central pallor) in blood smear
Eosin-5-maleimide binding test (EMA); Test of choice to confirm
Positive osmotic fragility test
degrees of salt dilution (e.g., RBCs swell and eventually lyse when incubated in hypotonic saline due to water

o positive means RBCs are more fragile and more vulnerable to osmotic stress

Treatment: splenectomy; definitive treatment

Prevents RBCs from being lysed by splenic macrophages

Complication

Megaloblastic anemia: folate and vitamin B12 deficiency may develop due to chronic hemolysis and high RBC
turnover
Hemoglobinopathies
Sources: AMBOSS, , Step-up to Medicine, The slides.

Objectives
Knowledge Cognitive Skills
1. Outline the clinical pictures of SCD and Thalassemia 1. Choose the most appropriate investigations to diagnose
hemoglobinopathies (blood tests) based on the available clinical
data
2. Outline the management of thalassemia. 2. Interpret blood tests (CBC with differential, peripheral blood
film, hemolytic work up, hemoglobin electrophoresis, sickling test)
3. Identify the complications of thalassemia. Describe the acute 3. Develop an evidence-based long-term management plan for
complications of SCD (acute chest syndrome and stroke) and sickle cell disease and thalassemia
outline their management. And identify the chronic complications
4. Recognize the types of crises in SCD and their management 4. Develop an evidence-based management plan for sickle cell
disease crisis
5. List the indications of exchange transfusion in SCD 5. Appropriately prioritize referral to Hematology Clinic.

Sickle cell
Pathophysiology
Sickle cell disease is a genetic disease where the blood cells take the shape of a sickle, which allows them to more
easily be destroyed causing hemolytic anemia, it results from single glutamate to valine substitution at position 6 of
the beta-globin chain gene at chromosome 11.

A hemoglobin with 2 alpha-globin and 2 mutated beta-globin is called sickle cell hemoglobin (HbS), which change
their shape when de-oxygenated and turn the RBC into sickle shape.

It is inherited as an autosomal recessive disease, patients who are sickle cell carriers (also called sickle cell trait) have

acidosis) which cause the percentage of HbS to go above 50% and cause symptoms.

Hemoglobin Normal Sickle cell trait Sickle cell disease

HbA 95-98% 60% 0%
HbS 0% 40% 75-95%
HbF <2% <2% 5-25%

HbF
HbA is composed of Alpha 2 and Beta 2, they do sickle as they have Beta chains

Note: oglobin (HbF)

Clinical presentation
1. Signs and symptoms of hemolytic anemia
Fatigue, dowseness, pallor
Jaundice (due to breakdown of RBCs and release of bilirubin)
Gallstones (due to high bilirubin which turns into bile)
Splenomegaly (due increased workload and obstruction of RBC in the spleen)
Hepatomegaly (due to increased workload to conjugate the bilirubin)
Skeletal changes (extramedullary hematopoiesis)
2. Symptoms related to Vaso-Occlusive crisis (Entrapment of the sickled RBC into the small blood vessels causing
occlusion and tissue ischemia and it is triggered by cold temperature, dehydration, overexertion and menses
(hormonal changes), infection and stress).
Dactylitis (hand-foot syndrome, occurs in kids): Painful, symmetric swelling of hands and feet, due to
ischemic necrosis of small bones
Acute chest syndrome (affects adults)
o Chest pain due to a new segmental lung infiltrates, and pleural effusion. Caused by pneumonia, bone
infarction, and fat embolism
o Other symptoms include: dyspnea, wheezing, and cough. ABG will show hypoxemia
o Acute chest syndrome is a medical emergency that requires blood transfusion
Sickle cell nephropathy
o Can cause a list of diseases including pyelonephritis, chronic kidney disease > cause diabetes insipidus
and End-stage renal disease
o Renal papillary necrosis
1. The papillae are in the medulla which is far away from the blood supply making it susceptible to
ischemia
2. Patient with sickle cell trait most likely have microscopic hematuria, while patients with sickle cell
disease have gross hematuria
o Chronic interstitial nephritis, causing inability to concentrate urine
Orthopedic diseases
o Avascular necrosis (commonly of the head of the femur)
o Osteomyelitis: Patients with sickle cell anemia have auto splenectomy, meaning they are more exposed
to infections. Salmonella is the most common organism
Auto splenectomy
o Occlusion causes ischemia and infarction of the spleen, causing loss of function and increasing the risk
of infection by encapsulated organisms (S. pneumoniae, H. influenza, Neisseria, and Salmonella) or
reduced tissue perfusion.
Spleen Sequestration
o Occlusion causes painful enlargement of the spleen and reduction in hemoglobin concentrations below

o Occurs before the spleen get fibrosed

o This is a medical emergency which may require blood transfusion
Aplastic crisis
o Hemoglobin is usually far below a patient's baseline and reticulocyte count is low.
o Infection with parvo B19 leads to pure red cell aplasia
o Bone infarction leads to pancytopenia
o Self-limited and transfusion is needed.
Recurrent leg ulcer
Proliferative retinopathy
Stroke in patients from 2-16 years
Priapism: a prolonged painful erection in men which occurs without sexual stimulation.
Venous thromboembolic disease

3. Sickle cell crisis (causes of acute presentation)

Vaso-occlusive crisis
Aplastic crisis
Splenic sequestration crisis
Hemolytic crisis (especially if the patient has G6PD)
Diagnosis
Neonatal screening (mandatory in all states)
If positive: Repeat hemoglobin electrophoresis (gold standard) confirms the diagnosis.
Peripheral blood smear
Sickle cells (drepanocytes): crescent-shaped RBCs
Target cells
Possibly Howell-Jolly bodies
Reticulocytotic
Disease monitoring
Laboratory analysis CBC for hemolytic anemia, LDH, reticulocytes, liver and renal function tests
Pulmonary function test
Transcranial doppler ultrasound is used to identify and monitor children with high risk of stroke
Imaging: X-ray of the skull shows hair-on- rythropoietic bone
marrow hyperplasia (also present in thalassemia).

Long term management

Prevent infections
Pneumococcal vaccines
Meningococcal vaccines
Daily penicillin prophylaxis (at least until the age of 5 years)
Prevent vaso-occlusive crises and manage anemia
Avoid triggers
Hydroxyurea: first-line treatment
Indications
Frequent, acute painful episodes or other vaso-occlusive events and hospitalization
Severe symptomatic anemia
sickled hemoglobin is proportionally
-occlusive episodes
Possible adverse effects: myelosuppression (beneficial in patients with myeloproliferative disease,
polycythemia vera)
L-glutamine: first approved treatment for pediatric sickle cell anemia
Indications: recurrent, acute complications of sickle cell disease

Possible adverse effects: constipation, nausea, headache, cough, pain (abdominal, back, chest)
Folic acid supplementation
Cholecystectomy to treat cholelithiasis
Splenectomy or partial splenectomy to prevent recurrent splenic sequestration.

Management of acute sickle cell crisis

Supportive treatment
Hydration with IV fluids and Oxygen
Pain management with NSAID and opioids
Thromboembolic prophylaxis
Blood transfusion
Indications:
Acute, severely symptomatic anemia
Secondary prophylaxis (acute chest syndrome, stroke, acute multiorgan failure)
Surgery (preoperative transfusion)
Pregnancy
 Exchange transfusions (erythrocytapheresis): automated removal of erythrocytes containing HbS and
simultaneous replacement with HbS free erythrocytes.
Indication: acute vaso-occlusive crisis (stroke, acute chest syndrome, acute multiorgan failure), splenic
sequestration crisis

Curative therapy
Allogeneic bone marrow transplantation
Indications: homozygotes, children < 16 years with severe disease

Acute chest syndrome management

Hydration and pain control
Antibiotics (3rd generation of cephalosporin with macrolide OR fluoroquinolone)
Oxygen and use incentive spirometry
Simple or exchange transfusion depends on the severity of the symptoms

Stroke prevention
For all children with HbSS or HbSBeta 0, a transcranial doppler is done yearly from 2 - 16 years of age
if it is abnormal, the patient begins chronic transfusions or exchange transfusions to keep their Hb S <30%
Without primary stroke prevention, 20-35% of children with HbSS have silent cerebral infarcts
Cognitive decline
Predisposes them to additional silent infarcts and overt strokes

Thalassemia
Definition
Are a group of hereditary (Autosomal recessive) hemoglobin disorders (Microcytic hypochromic anemia)
- -globin chains of hemoglobin (resulting in alpha or
beta-thalassemia).

It is caused by gene mutations

-globin locus - short arm of chromosome 11)
-globin gene cluster is
located on chromosome 16)

General Clinical Presentations/Complications for Thalassemia

1. Anemia: mild asymptomatic (carrier state) to severe in the major phenotype.
2. Hemolytic symptoms: Jaundice and gallstones
3. Skeletal deformities: secondary to extramedullary ineffective erythropoiesis
4. Iron overload: in transfusion-dependent thalassemia patients.
5. Endocrinopathies: secondary to iron overload
a. Hypogonadism
b. Growth impairment
c. Hypothyroidism
6. Cardiac: Heart failure/Arrhythmias
7. Pulmonary hypertension
8. Hepatosplenomegaly
9. Thrombosis and leg ulcer

There are 4 subunits of globin: 2 alpha and 2 beta and 4 heme groups which consist of (Iron and protoporphyrin)
Beta thalassemia: - -chains bind to and damage the RBC membrane
and the severity depends on the mutations):

1. -thalassemia major -chain thalassemia, two defective alleles)

a. Clinical presentation
Severe anemia beginning in late infancy
Jaundice and dark urine
Massive hepatosplenomegaly
Expansion of marrow space - -
x-ray
Skeletal deformities (high forehead, prominent zygomatic bones, and maxilla)
Growth retardation and failure to thrive
If untreated, death occurs within the first few years secondary to progressive congestive heart failure.
b. Diagnosis
Hemoglobin electrophoresis - reveals elevated HbF and HbA2
Peripheral blood smear - reveals microcytic, hypochromic anemia; target cells
c. Treatment
Frequent PRBC transfusions are required to sustain life

2. -thalassemia minor -chain thalassemia, one defective allele)

a. Asymptomatic carrier state or mild anemia
b. Diagnosed with hemoglobin electrophoresis
c. Peripheral blood smear reveals microcytic, hypochromic RBCs
d. Treatment not necessary

3. -thalassemia intermedia
a. Anemia of varying severity
b. Diagnosed with hemoglobin electrophoresis
c. Peripheral blood smear reveals microcytic, hypochromic RBCs
d. Most individuals are not transfusion-dependent in childhood but many will become transfusion-dependent
in adulthood.

4. Sickle cell beta thalassemia -globin allele and one defective HbS allele)
a. Features of sickle cell disease
b. -globin synthesis.

Alpha thalassemia: - -chains f

1. Silent carriers - locus):

a. Asymptomatic
b. Normal hemoglobin and hematocrit levels
c. No treatment is necessary
2. -thalassemia trait/minor -loci):
a. Mild hemolytic anemia
b. Peripheral blood smear reveals microcytic, hypochromic RBCs or can be normal RBC and RDW.
c. No treatment is necessary
3. Hemoglobin H disease
(mutation/deletion of 3 - - -4 hemotetramers):
a. Jaundice and anemia at birth
b. Anemia of varying severity
c. Hemoglobin electrophoresis shows Hb H
d. Peripheral blood smear reveals microcytic, hypochromic RBCs
e. Hepatosplenomegaly
f. Can require periodic transfusions during episodes of increased hemolysis such as in infection and secondary
iron overload due to hemolysis.
4. Hb-Bart's hydrops fetalis syndrome
- - -tetramers):
a. Most severe variant of alpha thalassemia
b. Intrauterine ascites and hydrops fetalis, severe hepatosplenomegaly, and often cardiac and skeletal
anomalies
c. Incompatible with life either fatal at birth or shortly after birth
d. No effective erythropoiesis due to

Diagnostics tests for thalassemia

Initial investigations
CBC
Characteristic finding: microcytic hypochromic anemia (MCV < 80 fL, MCH < 27 pg/cell) present
regardless of Hb level
Hb levels: variable depending on the subtype
Other red cell indices (Normal RDW and Higher RBC count than iron deficiency anemia)
Hemolysis evaluation: non-immune-mediated hemolytic anemia
Coombs test: negative

Liver chemistries: hyperbilirubinemia (indirect)

Iron studies (particularly ferritin): expected to be normal in thalassemia
Peripheral blood smear findings include:
HbH inclusion bodies
Target cells
Teardrop cells

Erythroblasts (An immature, nucleated erythrocyte precursor)

Basophilic Stippling

Important note: CBC parameters can help differentiate thalassemia minor/trait from iron deficiency anemia.
IDA is frequently associated with a high RDW, low RBC count, and low MCV typically occurring once the Hb is < 10
g/dL. In thalassemia, microcytosis is always present regardless of the Hb level, the RDW is typically normal, and
compared to IDA, the RBC count is higher and the MCV is lower.

Confirmatory diagnostic studies: Detection of hemoglobin variants

Hb-electrophoresis (qualitative analysis to establish the diagnosis), Findings (vary depending on the subtype):
Hemoglobin A (and subtypes): hemoglobin A2 values are helpful to determine the diagnosis (to distinguish

Hemoglobin F: may be elevated in some children and adults with thalassemia

Genetic studies: to determine specific diagnosis and mutations (Confirm genotype).
General Management for thalassemia
1. Patient education, genetic counseling and screening for family members
2. Folic acid supplement for thalassemia minor (during pregnancy, acute infections for example).
3. Regular transfusion in thalassemia major to maintain Hb 9-10g/dL
a. Indication (for transfusion-dependent thalassemia): Hb < 7 g/dL or marked clinical symptoms
4. Initiation of iron chelation therapy once indicated (Iron overload diseases)
5.
6. Hematopoietic stem cell transplantation (curative)

Follow-up plan
1. Repeated CBC depending on the severity
2. Iron study depending on the frequency of blood transfusion
3. Screening tests to check for complications
Thrombocytopenia
Sources: AMBOSS, , Step-up to Medicine, The slides.

Objectives (of thrombocytopenia and MAHA)

Knowledge Cognitive Skills
1. Describe thrombocytopenia and immune thrombocytopenia (ITP) 1. Choose the most appropriate investigations to diagnose
thrombocytopenia (blood tests and bone marrow) based on the
available clinical data
2. Recognize the causes of thrombocytopenia 2. Interpret blood tests (CBC with differential, peripheral blood
film, coagulation profile, fibrinogen, hemolytic work up,
hepatitis and HIV screen, autoimmune screen)
3. Develop clinical approach and management for 3. Formulate and prioritize a differential diagnosis for
thrombocytopenia (ITP) thrombocytopenia
4. Describe the basic pharmacology of medications used in immune 4. Develop an evidence-based management plan for immune
thrombocytopenia (ITP) (steroid and IVIG) thrombocytopenia (ITP) taking into consideration the advantage
and side effects of each modality
5. Identify the indications for bone marrow biopsy in immune 5. Appropriately prioritize referral to Hematology Clinic
thrombocytopenia (ITP)

Knowledge Cognitive Skills

1. Describe the pathophysiology and causes of MAHA, thrombotic 1. Choose the most appropriate investigations to diagnose MAHA
thrombocytopenic purpura (TTP), Hemolytic Uremic syndrome (blood tests) based on the available clinical data
(HUS) and disseminated intravascular coagulation (DIC)
2. Differentiate between thrombotic thrombocytopenic purpura 2. Interpret blood tests (complete blood counts CBC with
(TTP), Hemolytic Uremic syndrome (HUS) and disseminated differential, peripheral blood film, coagulation profile, fibrinogen,
intravascular coagulation (DIC) hemolytic work up, Direct antiglobulin test DAT, ADAMST13,
complement level)
3. Outline the basic management options for thrombotic 3. Formulate and prioritize a differential diagnosis for MAHA,
thrombocytopenic purpura (TTP), Hemolytic Uremic syndrome develop an evidence-based management plan for MAHA, and
(HUS) and disseminated intravascular coagulation (DIC) appropriately prioritize referral to Hematology Service

Definition: a condition in which you have a low blood platelet (thrombocytes) count: less than 150,000/uL
(normal: 150,000-450,000)

Degrees
Mild (>100,000): typically no bleeding, asymptomatic
Moderate (20,000-70,000/uL): high risk of surgery, see below
Severe (<20,000/uL): minor spontaneous bleeding, bruising, petechiae, epistaxis, menorrhagia, bleeding gums
Extreme (<5,000/uL): major spontaneous bleeding

Note: unlike coagulation disorders (e.g., hemophilia), deep tissue and joint bleeding are not seen, as only 1ry
hemostasis is affected

Risk of bleeding
Surgical bleeding is a risk when the platelet count is less than 50,000/uL. Less than 100,000/uL for neurosurgery
Spontaneous bleeding is a risk when the platelet count is less than 10,000-20,000/uL
Causes of thrombocytopenia
Redistribution, dilution,
Decreased production Increased peripheral destruction
and other causes

Bone marrow failure Immune thrombocytopenia (ITP) Sequestration

Bone marrow suppression Disseminated intravascular coagulation (DIC) (splenomegaly)
Congenital thrombocytopenia (e.g., Thrombotic thrombocytopenic purpura (TTP) Liver disease
Alport syndrome, Bernard-Soulier Drug-induced immune thrombocytopenia: Thrombocytopenia
syndrome, von Willebrand disease) antiplatelet, anticoagulants (heparin) antibiotics, following transfusion or
Infection (e.g., CMV, EBV, antiepileptic, antipsychotic, chemotherapy fluid resuscitation
parvovirus B19, Hepatitis C, HIV) Pregnancy: preeclampsia and HELLP syndrome Pulmonary embolism or
Malignancy Mechanical damage (e.g., dialysis) pulmonary hypertension

Important note: False or pseudo thrombocytopenia can be the cause of the low platelet count. It is caused by
platelets forming a clump causing a false reading.

Laboratory
Repeat CBC (to confirm)
Peripheral blood film (pseudo thrombocytopenia, schistocytes, WBC and RBC morphology)
Bleeding time, PT, PTT (will be prolonged in coagulation disorders)
Investigate for the underlying cause:
o Serology (HIV, HepC)
o Liver Function Test (LFT)
o Coagulation profile (DIC)
o Others (LDH, Renal function, Bone marrow biopsy)

Thrombocytopenia associated with bleeding Thrombocytopenia associated with thrombosis

Immune thrombocytopenia Disseminated intravascular coagulation (DIC)

Drug induced Thrombotic thrombocytopenic purpura (TTP)
Infections Heparin induced thrombocytopenia (HIT)
Malignancy of bone marrow

Treatment:
Treat the underlying cause, stop causative medications if present
Platelet transfusion might be needed depending on cause and severity

Immune Thrombocytopenic Purpura (ITP)

It is an autoimmune condition in which the body produces IgG auto-antibodies against its own thrombocytes or
platelets receptor (GP2b/3a) which leads to destruction of platelets and this results in purpura or small bleeding
spots beneath the skin
It is an acquired thrombocytopenia that is defined as a platelet count is <100x109/L
More common in female and younger adults
In a normal situations, when there is kind of damage to the blood vessels the hemostasis occurs (a process that stops
the bleeding and plugs the damaged vessel to limit the blood loss) in 2 steps
1. Primary hemostasis
Platelets aggregation to form a plug on the damaged vessel
2. Secondary hemostasis
Clotting factors will do the coagulation and cleave the fibrinogen to fibrin (act as a mesh) to cover a platelet
plug and stabilizes it
In ITP, the spleen produces IgG auto-antibody which binds to the platelet receptor (GP2b/3a) and targets the platelet
antibody complexes for the destruction in the spleen this leads to:

Low platelet counts in the blood which makes it harder for bleeding to stop
In conclusion, Antiplatelet antibodies (mostly IgG directed against, GpIIb/IIIa) bind to surface proteins on

production increase in response (in most cases)

In some cases, platelet production may be impaired because of destruction within the bone marrow or
inhibition of megakaryocytopoiesis

Acute ITP Chronic ITP

Affects Children (< 5 years of age) a couple

Female of reproductive age (20 to 40 years of age)
weeks after a viral infection

Course Resolve spontaneously within

Persist more than 6 months
2 months (self-limiting)

Primary
Types No trigger
Secondary
Triggered by another condition (Hepatitis C, HIV and lupus)

Clinical features of ITP: Clinical features can correlate with platelet count
Most commonly is asymptomatic and splenomegaly is typically absent.
Common:
Pin-Point Purpura (red or purple spots on the skin)
Measuring 0.3 to 1 cm in diameter
cytopenia
Subcutaneous bleeding: Petechiae, ecchymosis and bruising
In severe cases of ITP, platelets level will be very low and a frequent mucosal bleeding will happen which most
commonly presents as epistaxis
Other types of bleeding (rare)
Gastrointestinal: e.g., melena
Genitourinary: e.g., hematuria, menorrhagia
CNS: e.g., features of intracranial hemorrhage
Prolonged or excessive traumatic or surgical bleeding

Types of ITP
Primary immune thrombocytopenia
An autoimmune disorder characterized by isolated thrombocytopenia (<100,000/mm3) with no known
precipitating cause
It is a pathologic antiplatelet antibody, impaired megakaryocytes production and T-cell mediated destruction
of platelets is present
Secondary immune thrombocytopenia
An autoimmune hematologic disorder causing isolated thrombocytopenia that is secondary to an identifiable
trigger (e.g., Autoimmune, HIV and heli against
Etiology of ITP:
Primary ITP: idiopathic (most common)
Secondary ITP associated with:
Autoimmune disorders: SLE, antiphospholipid syndrome
Malignancy: lymphoma, leukemia (particularly CLL)
Infection: HIV, HCV
Drugs: e.g., quinine, beta-lactam antibiotics, carbamazepine, heparin, vaccines, sulfonamides,
vancomycin, antiepileptics

Diagnosis of ITP:
ITP is a diagnosis of exclusion; they typically have a low platelet count with no other abnormalities and there is
no specific test that confirms the diagnosis of ITP
Complete blood count (CBC) it will show isolated thrombocytopenia with a normal hematocrit and leukocyte
count
If there was a significant bleeding it can lead to anemia

Coagulation panel: usually normal

Bleeding time: may be prolonged
Peripheral blood smear: reveals decreased platelets
Abdominal ultrasound is done to rule out splenomegaly
Hepatitis C, HIV testing are done to rule out secondary ITP
Consider bone marrow aspiration in atypical cases, in suspicion of Myelodysplastic syndromes and malignancy
Normal finding: normal or high megakaryocytes (number and size)
Additional testing as required: consider in suspected secondary ITP
Antinuclear antibodies in SLE
H. pylori testing if the patient has GI symptoms or is from a high prevalence area

General treatment of ITP

When to treat?
Platelet <30,000 with or without bleeding
To achieve target platelet counts prior to surgery
In an acute bleeding

Primary ITP Treatment

The treatment depends on the platelet count and symptoms:
Asymptomatic
Platelet count >30,000
Treatment: Observed and often recover on their own
Patient with an active bleed
Or platelet count <30,000
Treatment: start on corticosteroids (act as immunosuppressant) or
immunomodulatory effect) and they both stop the formation of new Autoantibodies
If the patient does not respond to steroids, a splenectomy can be done to get rid of the splenic
macrophages that are destroying the platelets
Transfusing platelet can be done when platelet counts is <30,000
 Secondary ITP Treatment
They are treated for their underlying condition

Management Review management approach for ITP

All patients Identify and treat underlying causes.
Consider stopping medications that impair platelet function, e.g., NSAIDs.

Patients requiring emergency treatment: Attempt hemostatic control if bleeding is present.

Start combination therapy:
Life-threatening bleeding Corticosteroids: e.g., methylprednisolone
Acute neurological features PLUS intravenous immunoglobulin (IVIG)
Anticipated urgent surgery or invasive PLUS platelet transfusions as needed
procedure If no response, consider a thrombopoietin receptor agonist (TPO-RA) or
splenectomy

Patients with: Conservative management preferred for:

No symptoms Children with any platelet count

Only minor mucocutaneous bleeding First-line medical therapy: indicated for adults with platelet count <
30,000/mm3

Patients with: First-line medical therapy

Indicated for adults
Significant non-life-threatening mucosal Can be considered in children
bleeding (severe epistaxis) Consider subsequent therapeutic options if refractory to first-line medical
Symptoms impacting quality-of-life therapy.

Important Note:
Indications for observation:
Children: no symptoms or only mild mucocutaneous bleeding with any platelet count

First-line medical therapy:

Preferred: Corticosteroids
Alternatives: if contraindication, non-response, or intolerance to corticosteroids
Intravenous immunoglobulin (IVIG)
OR anti-Rho(Anti-D) immunoglobulin
Second-line therapy:
-
In splenectomy-resistant patients you give:

Platelet transfusion for patients with severe bleeding and platelet counts <30,000
Microangiopathic Hemolytic Anemia (MAHA)
A type of extrinsic hemolytic anemia that is the result of mechanical damage to erythrocytes by microthrombi in
small blood vessels (intravascular). Characterized by schistocytes on the peripheral blood smear

Causes
Primary (occurs spontaneously; not associated with a specific underlying condition)
o Thrombotic Thrombocytopenic Purpura (TTP)
o Hemolytic Uremic Syndrome (HUS)
Secondary (Associated with an underlying condition)
o Disseminated Intravenous Coagulation (DIC)
o Autoimmune disease (e.g., SLE)
o HELLP syndrome: a form of pregnancy-induced hypertension (Preeclampsia) with the following features:
H: Hemolysis
EL: Elevated Liver enzymes
LP: Low Platelet

Pathophysiology
Systemic microthrombi plugs the small vessels causing physical intravascular damage to the RBCs that pass through
the small vessels. Which then causes intravascular hemolysis, Schistocyte, and high free hemoglobin. It is
characteristically accompanied by thrombocytopenia

Clinical presentation
Features of anemia (e.g., pallor, fatigue)
Jaundice
Organ dysfunction due to microthrombi formation (e.g., renal dysfunction, altered mental status)
Petechiae due to thrombocytopenia

Diagnosis
Consider MAHA in patients with the following:
CBC showing anemia and thrombocytopenia
Laboratory evidence of hemolysis with negative DAT
PBS showing abundant schistocytes

Thrombotic Thrombocytopenic Purpura (TTP)

ts

Risk factors
Systemic disease: cancer, HIV, SLE, infections

Pathophysiology
TTP is a thrombotic microangiopathy:

Autoantibodies or gene mutation cause deficiency of ADAMTS13 enzyme which is responsible for cleavage of
von Willebrand factor
Decreased breakdown of vWF multimers which causes them to accumulate on endothelial cell surfaces
Platelet adhesion causing microthrombosis, which leads to hemolytic anemia as explained above

Clinical features
The pentad of clinical findings is in the Nasy Fever Ruined My T
N: Neurologic symptoms (Altered mental status: delirium, stroke, headache)
F: Fever
 R: Renal function impairment
o Hematuria, proteinuria
M: Microangiopathic hemolytic anemia (MAHA)
o Fatigue, dyspnea, jaundice
T: Thrombocytopenia
o Petechiae, purpura
o Prolonged bleeding after minor cuts
Note: impaired kidney injury may not be present, only a minority of patients present with all 5 clinical findings

Diagnosis
Hematology:
Low platelets, hemoglobin, and haptoglobin
Elevated reticulitis
Normal or mildly prolonged PT and aPTT
Negative Coomb (non-immune)
Peripheral blood smear:
Schistocytes (important)
Low number of platelets
Serum chemistry:
High LDH, and high indirect bilirubin
High BUN, and high creatinine
ADAMTS13 activity and inhibitor testing
Low ADAMTS13 activity (<10%)
Identification of secondary causes (e.g., tests for pregnancy, SLE, HIV, cancer)

Treatment
Plasma exchange is the gold standard, fresh frozen plasma can be used temporarily
Steroid, Rituximab can be used
Note: TTP requires urgent diagnosis and treatment, waiting for test results to confirm ADAMTS13 deficiency should
not delay treatment

Hemolytic Uremic Syndrome (HUS)

and occlude the arterioles and capillaries. These occlusions result in the simultaneous occurrence of
microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury (AKI).

Epidemiology: Mainly children < 5 years of age

Etiology
Bacterial exotoxins
Shiga-like toxin (verotoxin)
From enterohemorrhagic E. coli (EHEC) strain O157:H7
Usually transmitted via contaminated foods (e.g., undercooked beef or raw leafy vegetables)
Shiga toxin produced by Shigella dysenteriae
Streptococcus pneumoniae infection
Atypical hemolytic uremic syndrome: Complement dysregulation (hereditary or acquired) cases with
noninfectious etiologies (aHUS).
General pathophysiology
- - -
-organ damage,
especially in the

Clinical features
A patient is a preschooler who has had diarrheal illness (usually bloody) for the past 5 10 days precedes the
onset of HUS symptoms. The triad of clinical findings occurring in HUS consists of:
Thrombocytopenia
Petechiae, purpura
Mucosal bleeding
Prolonged bleeding after minor cuts
Microangiopathic hemolytic anemia
Fatigue, dyspnea, and pallor
Jaundice
Impaired renal function
Hematuria, proteinuria
Oliguria, anuria

Important note:
TTP involves the HUS triad of symptoms plus two additional ones: fever and neurological symptoms.
Impaired renal function is more common in HUS than TTP.
Atypical HUS happens to adults with no diarrhea

Diagnostics
Hematology
Hemolytic markers
Hemoglobin, Haptoglobin,

Normocytic normochromic anemia

Coagulation profile
Platelets,
Normal/slightly elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT)
Normal/slightly elevated Fibrin degradation products and D-dimer levels

Negative Coombs test

Urinalysis: hematuria, proteinuria

Treatment
Supportive care
Avoid antibiotics and antimotility agents (may increase the likelihood of HUS in suspected infection with
EHEC)
Monitor and correct:
Fluid status abnormalities, electrolyte disturbances and Acid-base abnormalities
Blood pressure (HUS can cause hypertension or septic shock.)
RBC transfusions (In severely anemic patients)
Dialysis (as indicated for AKI)
 Plasma exchange therapy: only in refractory cases
Eculizumab
Effective for the treatment of aHUS
May be beneficial in HUS with neurological symptoms

Important note: Platelet transfusions should be administered with caution unless patients are bleeding or
require an invasive procedure because some studies suggest that they can exacerbate microangiopathy.

Complication
CNS (e.g., Seizures, stroke)
GI tract (e.g., Bowel necrosis, perforation, stricture, peritonitis, Intussusception)
Heart: ischemia and fluid overload
Pancreas: transient or permanent diabetes mellitus
Liver: hepatomegaly
Kidney (Hypertension, Chronic kidney disease [CKD])

Disseminated Intravascular Coagulation (DIC)

a syndrome characterized by thrombosis, hemorrhage, and organ dysfunction caused by systemic activation of the
clotting cascade, which leads to platelet consumption and exhaustion of clotting factors

Causes
Sepsis (commonly gram-negative organisms especially meningococcal)
Trauma (acute traumatic coagulopathy, burns)
Obstetric complications (amniotic fluid embolism, abruptio placenta)
Organ failure (acute pancreatitis, acute respiratory distress syndrome [ARDS])
Malignancies
Toxins (e.g., snake venom, drugs)
Immunologic (severe allergic reaction, transplant rejection)

Clinical features
Patients will have simultaneous bleeding and thrombosis as well as organ failure. The clinical features will depend on
the sites affected

Diagnosis
Coagulation panel (monitor frequently)
High aPTT, PT, D-dimer, and bleeding time
Low Fibrinogen

CBC and blood smear

Low platelet count, and Hct
Schistocyte

Note: Thrombocytopenia, elevated D-dimer, increased PT and aPTT, and low fibrinogen should immediately raise
suspicion for DIC.

Management
Treat the underlying disorder
Supportive:
Platelet transfusion if bleeding (avoid if not bleeding)
Fresh frozen plasma + cryoprecipitate if bleeding
Bleeding Diathesis
Sources: AMBOSS, , Step-up to Medicine, The slides.

Objectives
Knowledge Cognitive Skills
1. Describe the clinical features of hemophilia 1. Choose the most appropriate investigations to diagnose inherited
bleeding disorders (blood tests) based on the available clinical data
2. Outline the diagnostic tests of hemophilia 2. Interpret blood tests (CBC with differential, coagulation profile,
mixing studies, coagulation factors and vWF assay)
3. Outline the treatment plan in hemophilia 3. Formulate and prioritize a differential diagnosis for inherited
bleeding disorders
4. Identify the possible complications of hemophilia 4. Develop an evidence-based management plan for inherited
bleeding disorders and understand the pharmacology of
desmopressin dDVAP
5. Describe the clinical picture and the diagnosis of vWD 5. Appropriately prioritize referral to Hematology Clinic
6. List types of vWD 6. Demonstrate the appropriate skills for patient education
7. Distinguish between fresh frozen plasma (FFP),
Cryoprecipitate, Factor VIII concentrate and von Willebrand
factor (vWF) concentrates

Hemophilia
What happens when you bleed? You Clot!
Steps of hemostasis (stop the flow of blood):
1. Vasoconstriction: Limitation of the blood flow
2. 1ry hemostasis: Temporary platelet plug formation
3. 2ry hemostasis: Coagulation cascade activation > formation of fibrin and stabilization of the platelet plug
4. Fibrinolysis: Dissolves the clot and restores the function
5. Regeneration (Repair)

Clinical features of 1ry hemostasis disease

Asymptomatic
It may cause superficial bleeding (mucocutaneous)
o Skin bleeding (e.g., petechiae, purpura, ecchymosis)
o Mucosal bleeding (e.g., epistaxis, easy bruising, etc.)
o Important note: Petechial bleeding is a common sign of platelet disorders, but NOT of coagulation disorders
such as hemophilia.

Diagnostic tests for 1ry hemostasis disease

Platelet count (PC)
Bleeding time (BT): Reflects platelet function
Platelet Aggregometry

Clinical features of 2ry hemostasis disease

o Late re-bleeding (e.g., bleeding after tooth extraction, after surgery)

o Hemarthrosis (affecting the joints)
o Deep muscle bleeding
o Retroperitoneal bleeding
o Intracranial bleeding
o patients can also have superficial bleeding as well
Diagnostic tests for 2ry hemostasis disease
PT (prolonged in extrinsic pathway pathology)
o Prolonged by anticoagulants (e.g., warfarin)
aPTT (prolonged in intrinsic pathway pathology)
o Prolonged by anticoagulants (e.g., heparin)
TT (prolonged in common pathway pathology), (Measures of fibrinogen concentration)

The problem in hemophilia is: step number 3 of hemostasis which is the coagulation cascade activation (2ry
hemostasis) step causing an intrinsic pathway problem (factors 8,9 and 11) resulting in a prolonged aPTT but the PT
of the extrinsic pathway will be normal.

Causes of hemophilia
1. Decrease in the amount of a clotting factor
2. Decrease in the function of a clotting factor

Diagnostic tests for hemophilia

Lab tests
Platelet count, will be normal
Prothrombin time (PT): tests the extrinsic & common pathways (factor 1,2,5,7 and 10) will also be normal
Partial thromboplastin time (PTT or aPTT): tests the intrinsic & common pathways (1,2,5,8,9,10,11 and 12)
will be prolonged in hemophilia
If the aPTT is prolonged do -> Mixing study (best initial test): Which is mixing the patient's plasma with normal
plasma to differentiate between the factor deficiency or the presence of an inhibitor against the factor
(Antibody)
If the prolonged aPTT is caused by a lack of clotting factors, the factors contained in the normal plasma will
normalize the aPTT of a hemophilia patient. In the presence of a clotting inhibitor such as lupus
anticoagulant, the clotting time (aPTT) remains increased or fails to normalize
If a mixing study is positive -> quantitative assessment of factor activity levels (factor assay) should be done
(Most accurate test)
Confirmation tests for specific factor activities and mutation testing the genes encoding them.

Treatment of hemophilia
Injection of the missing or nonfunctional clotting factor
Substitution of
Factor 8 concentrate for hemophilia A
Factor 9 concentrate for hemophilia B
Factor 11 concentrate for hemophilia C
if unavailable, use cryoprecipitate
But if the patient has severe deficiency, where intrinsic production of the factor is absent or very low due to
inhibitors (antibodies) against the factors which can diminish the effectiveness of the treatment over time
and it may cause anaphylaxis - allergic reaction.
Avoid contact sports and certain medications that promote bleeding like antiplatelet (Aspirin).
Genetic counseling
RICE - Rest, Ice, Compression and elevation.
Prophylaxis for severe patients (with less than 1% factor) prior to aggressive activities.

Hemophilia A (Classic hemophilia)

-linked recessive (almost always in males, but female are carriers and sometimes they can have mild
symptoms). caused by decrease in factor 8 activity (antihemophilic factor) either due to deficiency of the factor
or inhibitor working against the factor.

Hemophilia A is usually the worst because it is the common type and most of the patients have severe disease.
Diagnostics
Platelet count, bleeding time, PT will all be normal
PTT, and coagulation time: prolonged
TT: normal, could be prolonged
Factor 8 activity: low
vWF level: normal
Factor 8 level:
Low if the cause is deficiency
Normal if the cause is inhibition
Mixing study
Normal if the cause is deficiency
Remains unchanged if the cause is inhibition

Treatment
Factor 8 replacement (can be administered episodically or continuously)
Emicizumab (humanized monoclonal bispecific antibody)
Mechanism of action: bridges activated factor 9 and factor 10 by binding to both factors (thereby replacing
the deficient factor 8)
Desmopressin (DDAVP;1-desamino-8-d-arginine vasopressin)
it is helpful for mild factor 8 deficiency
it stimulates vWF release from the endothelial cells which promotes the stabilization of the residual factor 8

Notes:
Von Willebrand disease mimics hemophilia A but it is caused by primary or secondary hemostasis problem
and in severe cases of vWF disease, factor 8 gets broken down faster
and becomes deficient because vWF stabilizes factor 8 in the intrinsic pathway.
Factor 8 circulates in blood bound to von Willebrand factor.

Hemophilia B (Christmas disease)

It is caused by decrease in factor 9 activity (Christmas factor) either due to deficiency of the factor or inhibitor
working against the factor, X-linked recessive disease

Diagnostics
Platelet count, Bleeding time and PT all will be normal
PTT: prolonged
Coagulation time: Prolonged
Factor 9 activity: Low
Factor 9 level: It depends if the patient has a deficiency (it will be low) or if there was an inhibitor working
against the factor (it will be at a normal level).
Mixing study: Either its a factor deficiency (results will be normalized) or a factor inhibitor is present (it will
remain unchanged)

Treatment
Administration of factor 9 concentrate
If the patient had inhibitor (antibodies) against factor 9: Give factor 9a (active form of factor 9)
DDAVP does NOT play a role in treatment.

Signs and symptoms of hemophilia A & B

They are nearly identical because factors 9a and 8a work together to activate factor 10:
History: presents as a young boy with spontaneous bleeding into the tissues, muscles and joints (hemarthrosis)
Easy bruising (Ecchymosis)
 Hematomas (Deep in the muscles)
Prolonged bleeding after a cut or a surgical procedure (e.g. circumcision).
Oozing after tooth extractions
Gastrointestinal bleeding (Retroperitoneal hematoma)
Hematuria (Blood in the urine) or hemospermia (blood in semen)
Severe nose bleeds (Epistaxis)
Oral mucosa bleeding
Hemarthrosis (Bleeding into joint spaces) knees are the most common site -> hemophilic arthropathy
Progressive joint destruction can occur secondary to recurrent bleeding.
Acute hemarthrosis treatment:
Analgesia (Avoid aspirin and NSAIDs)
Immobilization of the joint
Ice packs
Important note: the severity of the symptoms depends on the severity of the underlying mutation which
determines the activity or the amount of the factor.

Complications of hemophilia
Bleeding into the brain (causing stroke or increased intracranial pressure) and it is the common cause of death.
Osteoporosis
Viral infection
Crippling Arthropathy
Inhibitors (Development of autoimmune response with antibody development against the factor), Treatment:
Infusion of bypassing agent for bleeding: recombinant activated Factor 7 (rFVIIa) and plasma-derived
activated prothrombin complex concentrate. Instead of replacing the missing factor, they bypass the factors
that are blocked by the inhibitor to help the body form a normal clot.
Immune tolerance therapy: administration of factor 8 in increased doses so that the individual's immune
system learns to tolerate the factor 8 and ceases to produce inhibitors (for hemophilia A).

Hemophilia C (Rosenthal syndrome)

It is caused by deficiency in factor 11 (Plasma thromboplastin antecedent; PTA), Autosomal recessive (Consanguinity;
Cousin marriage)
Tests
Platelet count, Bleeding time and PT all will be normal
PTT: prolonged
Coagulation time: Prolonged
Factor 11 activity: Low
Factor 11 level: It depends if the patient has a deficiency (it will be low) or if there was an inhibitor working
against the factor (it will be at a normal level).
Mixing study: Either its a factor deficiency (results will be normalized) or factor inhibitor is present (it will remain
unchanged)

Treatment
Plasma derived factor 11 concentrate
If the patient had inhibitor (antibodies) against factor 11: Give factor 11a (active form of factor 11)

Acquired causes of hemophilia

Liver failure; because it synthesizes factors (1,2,5,7,8,9,10,11 and 13)
Vitamin K deficiency; because it is needed by the liver to synthesize and release factors (2,7,9 and 10)
Autoimmunity against a clotting factor
Disseminated intravascular coagulation (DIC); which consumes coagulation factors
Von Willebrand factor (Also known as factor 8-related antigenic protein)
It is synthesized and stored in the endothelial cells and megakaryocytes.
Function:
1. Plays a role in forming blood clots
2. Platelet adhesion after being attached to the exposed collagen fibers that are located in the wall of an
injured blood vessel
3. Binds and stabilizes factor 8 to protect it from the degradation of protein C and S

Von Willebrand disease

It is the most common inherited bleeding disorder caused by dysfunction or deficiency of von Willebrand factor
which will increase the risk of bleeding. It is either autosomal dominant or recessive depending on the type, meaning
it affects both male and female patients unlike hemophilia

vWD is involved in both 1ry and 2ry hemostasis:

Impaired 1ry hemostasis: affection of adhesions of platelets will cause thrombasthenia: patients will have
abnormal platelet function (dysfunctional platelet adhesion), which manifests as a prolonged bleeding time,
despite having a normal platelet count.
Note: other causes of impaired platelet function includes uremia and the use of NSAIDs or aspirin.
Impaired 2ry hemostasis: vWF sustains and prolongs the ½ life of factor 8 by preventing its degradation, in vWD
the amount of factor 8 could be normal but their activity will be low.

Types of vWF disease

Inherited vWF disease (caused by mutation in the vWF gene) is classified into 3 main types:
Type 1 (Most common): Autosoma
production of vWF (mild to moderate deficiency of vWF and factor 8).
Type 2: Quantity is enough, but the problem is in the quality (Dysfunctional vWF), and it has 4 subtypes:
2A & 2M: attaches well to the subendothelial collagen and binds to factor 8 BUT unable to do platelet
adhesions to form a plug.
2B: vWF binds to platelets everywhere in the bloodstream even when there is no injury thus, the platelet
count will be low which is another risk of bleeding.
2N: Binds both the subendothelial collagen and does platelet adhesion BUT does not bind well with
factor 8. Therefore, factor 8 will be degraded quickly by protein C and S resulting in low factor 8 level in
the bloodstream and it will increase the risk of bleeding.

vWF).

Acquired Von Willebrand disease

They have normal vWF genes but yet they present with the symptoms (due to vWF deficiency secondary to other
medical conditions):
Autoimmune disorders (e.g. systemic lupus erythematosus where the body produces antibodies against self-
antigens including vWF it will be destroyed and its levels will drop in the bloodstream).
Lymphoproliferative and myeloproliferative diseases (e.g., multiple myeloma, monoclonal gammopathies,
lymphoma, essential thrombocythemia).
Cardiovascular defects (e.g., ventricular septal defect, aortic stenosis).
Some medications (Valproic acid and ciprofloxacin) interfere with the synthesis of vWF.
Symptoms of vWF disease (Depends on the type of the disease)
The clinical presentation involves symptoms of both intrinsic and extrinsic pathways

Inherited type 1 and 2 (A, B & M):

Often asymptomatic or have mild mucocutaneous bleeding (e.g.,
bleeds, Petechiae and Prolonged bleeding from minor injuries).
heavy menses (Menorrhagia which affects up to 92% of women with vWD).
Can be severe if the patient was taking anticoagulants, platelet antiaggregant medications (Aspirin) or
NSAIDs (celecoxib).
Inherited type 3 and type 2 (N):
Severe bleeding (Joint and muscle bleeding).

Increased bleeding after surgical procedures, tooth extraction or post-partum.

Acquired vWF disease:
New onset of bleeding on the background of some pathological conditions such as autoimmune disorders or
anticoagulants and platelet antiaggregant medications.

Diagnosis
History
Recurrent episodes of bleeding since childhood
prolonged bleeding noted after surgery or trauma
Often positive family history
Symptoms worsen with acetylsalicylic acid (ASA) use.
Platelet count (usually normal except in vWF disease type 2B which might be lower than normal)
Prothrombin time (PT): Normal because the extrinsic pathway factors work independently of vWF
Factor 8: is reduced in vWF disease
Activated partial thromboplastin time (aPTT)
Will be prolonged in affected people because it tests the intrinsic pathway which includes factor 8
Note: A normal aPTT does not exclude the diagnosis.
Bleeding time: Prolonged
vWF antigen levels: measures the amount of vWF present in the blood which will be low.
vWF activity done by using (ristocetin cofactor assay; Diagnostic test):
It measures the capacity of vWF to agglutinate platelets and detects vWF dysfunction.
When ristocetin is added to a plasma that contains normal working vWF, then ristocetin activates vWF to
bind the platelets (platelet adhesion) -> resulting invisible coagulation
In vWF disease results will be failure of platelet aggregation or a reduced ristocetin-induced platelet
aggregation (level <30 IU/dL).

Management
Treatment is only indicated if it is confirmed by laboratory diagnosis and symptoms occur
vWF disease (type 1 & 2):
They have bleeding episodes (minor bleeding/mild or moderate symptoms)? Give vasopressin analog
-
DDAVP: stimulates the endothelial cells and megakaryocytes to release vWF
If no response, give factor 8 concentrate
vWF disease (type 3/severe bleeding):
DDAVP does not help because there is a complete deficiency of vWF
Intravenous exogenous vWF concentrate in combination with factor 8 concentrates
Use as prophylaxis for surgical procedures or after major trauma.
Use if DDAVP treatment is ineffective.
 oral contraceptives for menorrhagia
Is it difficult to control the bleeding? give anti-fibrinolytic (e.g., Tranexamic acid) it helps to delay dissolution
of clots. Thus, it sustains the clots for a longer time to prevent bleeding.
Acquired von Willebrand disease:
Treatment of the underlying cause

Important note: Platelet aggregation inhibitors (e.g., aspirin, NSAIDs, clopidogrel) and intramuscular injections are
contraindicated in von Willebrand disease because they further increase the risk of bleeding!

Important notes about some treatments

Fresh Frozen Plasma (FFP): is rich in all coagulation factors and protein.
Used when there is a need for colloid.
Giver for high PT/PTT
Used for reversing coagulopathy and deficiency of coagulation factors.
Cryoprecipitate: Rish in fibrinogen and factor 8 with smaller concentration of vWF. It is used to prevent or
control bleeding in people whose own blood does not clot properly.
patients with serious but rare hereditary conditions such as Hemophilia A (who lack factor 8) and von
Willebrand disease (who lack von Willebrand factor).
High Blood Count
Sources: AMBOSS, Step-up to Medicine, The slides.

Objectives
Knowledge Cognitive Skills
1. Classify the etiology of high blood counts (leukocytosis, 1. Choose the most appropriate investigations to diagnose
erythrocytosis, thrombocytosis) elevated blood counts (blood, bone marrow, and imaging)
based on the available clinical data
2. Distinguish between benign and malignant causes of high 2. Interpret blood tests (CBC with differential, peripheral
blood counts blood film, erythropoietin level, JAK2 test)
3. Describe leukemoid reaction 3. Formulate and prioritize a differential diagnosis of
leukocytosis, erythrocytosis and thrombocytosis.
4. Outline the different clinical presentations of acute and 4. Appropriately prioritize referral to Hematology Clinic
chronic leukemia, polycythemia rubra vera, essential
thrombocytosis
5. Identify the clinical red flags associated with malignant 5. Demonstrate the appropriate skills for patient education
high blood counts.
6. List the complications associated with leukemia,
polycythemia vera and essential thrombocytosis
7. Outline the management for leukemia, polycythemia vera
and essential thrombocytosis

Leukocytosis
It is an elevation of the White Blood Cell count > 11,000/mm3

WBC types
Myeloid cell line: granulocytes (eosinophil/neutrophil/basophil), mast cells, and monocytes
Lymphoid cell line: lymphocytes (T cell, B cell, or NK cell)

Causes
Which WBC type is elevated the most depends on the trigger stimulus or injury.
Infections
Sepsis
Leukemia: leads to increased release of premature leukocytes into the blood
o Acute myeloid leukemia (AML)
o Acute lymphocytic leukemia (ALL)
o Chronic myeloid leukemia (CML)
o Chronic lymphocytic leukemia (CLL)
Autoimmune reactions
Drugs: e.g., lithium

Thrombocytosis
It is an absolute platelet count of > 400,000/mm3
Normally, 150,000 400,000/mm3 (150 400 x 10^9/L)

Causes
Reactive thrombocytosis: secondary to certain conditions, e.g.:
o Malignancy (e.g., CML)
o Splenectomy
o Chronic inflammation
Autoimmune diseases: e.g., rheumatoid arthritis, celiac disease, connective tissue disorders
Chronic infections: e.g., tuberculosis, syphilis
o Anemia: hemolytic anemia, iron deficiency
 o Increased cellular turnover following acute blood loss
o Pregnancy
Splenectomy
Essential thrombocythemia

Erythrocytosis
It is an elevation of the red blood cell count, reference range:
In male: 4.3 5.9 x 10^12/L
In female: 3.5 5.5 x 10^12/L

Causes
Polycythemia vera
Increased erythropoietin (EPO) synthesis, e.g., due to:
o Chronic hypoxia (e.g., in COPD or CHF)
o Malignancies (paraneoplastic effect)

Leukemoid reaction
Definition
Reactive leukocytosis: cell hyperplasia with proliferation of myeloid or lymphoid elements haracterized by
an increased leukocyte alkaline phosphatase (LAP) score (LAP is an enzyme found in mature leukocytes)

Causes
Infections (predominantly bacterial, e.g., pertussis)
Severe purulent conditions (e.g., perforated appendicitis)
Drugs (e.g., steroids)
Associated with certain solid tumors (e.g., lung cancer, renal cancer)

polycythemia rubra vera

Chronic myeloproliferative neoplasm that is characterized by an erythropoietin-independent, irreversible increase in
erythrocyte, granulocyte, and platelet counts.

Pathophysiology
The JAK2 (Janus kinase 2) is essential for the regulation of erythropoiesis, thrombopoiesis (megakaryopoiesis),
and granulopoiesis

erythropoietin- lood cell mass (erythrocytosis,

oxygenation.

Clinical features
Patients with PV are at increased risk of thrombosis and bleeding
Often asymptomatic
Constitutional symptoms: weight loss, fatigue, sweating
Hyperviscosity syndrome (triad of mucosal bleeding, neurological symptoms, and visual changes)
o Will cause Hypertension
Facial Plethora (Flushed face, Cyanotic lips)
Erythromelalgia
Aquagenic pruritus: Itching typically worsens when the skin comes into contact with warm water
Splenomegaly (Due to increased cell turnover)
Peptic ulcer disease (Due to excessive histamine production by mast cells)
Diagnostics

o In men: Hemoglobin level is >16.5 g/dL

o In female: Hemoglobin level is >16 g/dL
and

Evidence of a genetic mutation in the JAK2 gene

Treatment
First line treatment: Phlebotomy (mechanical reduction in the number of red cells)
o Periodic removal of blood via venapuncture temporarily reduces cell counts and hyperviscosity.
o Until a is established
Antiplatelet prophylaxis: low-dose aspirin
Cytoreductive therapy
embolism and advanced age >60) = patient is at high risk
o Hydroxyurea in addition to phlebotomy and aspirin
o JAK2 inhibitor: ruxolitinib (For patients resistant or intolerant to hydroxyurea)
o Interferon alpha

Complications
Thrombotic complications
o Venous thrombosis: DVT, Budd-Chiari syndrome
o Arterial thrombosis: Stroke, Myocardial infarction (MI)
Hemorrhagic complications
o Petechiae, Epistaxis and Bleeding gums
Gout
o due to high number of cell turnover which will increase uric acid
In late stage
o

Secondary polycythemia

Causes

High-altitude exposure
Renal cell carcinoma (RCC)
Hepatocellular carcinoma (HCC)
Use of androgen and diuretics

Essential thrombocythemia (ET)

Isolated uncontrolled proliferation of platelets not caused by another condition (e.g., reactive thrombocytosis)
Reactive thrombocytosis: A transient elevation in platelet count caused by an underlying condition (e.g.,
systemic infection, inflammation, malignancy, splenectomy).

Clinical features
Commonly asymptomatic
Vasomotor symptoms (headache, visual disturbances, acral paresthesia, ocular migraines)
Increased risk of fetal loss:
o ET is also associated with preeclampsia, intrauterine growth retardation, and stillbirth.
Livedo reticularis
Erythromelalgia (Red and painful hands or feet with warmth and swelling)
Thromboembolic events
Acute gouty arthritis (Due to high cell turnover)
Diagnostics
Isolated sustained thrombocytosis (> 450 x 10^9/L) and increase in megakaryocytes
o Bone marrow studies: hyperplasia of mature megakaryocytes
Absence of secondary causes of reactive thrombocytosis (Chronic inflammation, infection, cancer and iron
deficiency)
JAK2, CALR and MPL mutation (one of them will be present)
o JAK2 mutation helps to distinguish essential thrombocythemia from secondary thrombocythemia

Treatment
Low risk patients
o low-dose aspirin
High risk patients (age >60years old, history of previous thrombosis)
o low-dose aspirin + cytoreductive agents such as:
Hydroxyurea
Anagrelide
Interferon alpha
Platelet-pheresis is used when the platelet count must reduce quickly in a life-threatening situation such as
stroke, MI, TIA or GI bleeding
Complications
Venous or arterial clots
Acquired von Willebrand disease (aVWD)
Transformation to:
o Myelofibrosis
o Acute myeloid leukemia (AML)
Note:
The most common causes of thrombocythemia are iron deficiency anemia and infection
A negative JAK2 mutations does not exclude the diagnosis of ET

Acute leukemia
Are malignant neoplastic diseases that arise from either the lymphoid or myeloid cell line.

General features of acute leukemia

Sudden onset of symptoms and rapid progression (days to weeks)
Anemia: fatigue, pallor, weakness
Thrombocytopenia: epistaxis, bleeding gums, petechiae, purpura
Immature leukocytes: frequent infections, fever
Hepatosplenomegaly (caused by leukemic infiltration)
Oncologic emergencies can be the first sign of leukemia, e.g., An elderly patient presenting with priapism or DIC
may have leukostasis (more common in AML than ALL).
Diagnostics
Complete blood count
o Leukocytes: The white blood cell count (WBC) may be elevated, normal, or low and is not a reliable
diagnostic marker.
o Platelets; thrombocytopenia
o Hemoglobin: typically anemia
Peripheral blood smear: presence of blasts (immature WBCs)
Comprehensive metabolic panel and other metabolic studies
o Often abnormal due to increased cell lysis

In advanced therapy of acute leukemia

Autologous or allogeneic stem cell transplantation: Indications include patients with poor prognostic factors (e.g.,
unfavorable cytogenetics) and those who do not achieve remission with chemotherapy
Complications
Tumor lysis syndrome and Leukostasis
Types of acute leukemia
Acute lymphocytic leukemia Acute myeloid leukemia

Note The Most common malignant disease in children It is during adulthood, a peak incidence of age 65 years

Pre-existing hematopoietic disorder is the most

common identifiable cause:
Myelodysplastic syndromes
Etiology
Aplastic anemia
Myeloproliferative disorders (e.g.,
osteomyelofibrosis; CML)

Immunophenotype classification of ALL: based on

From M0 to M7-AML, the important one is Acute
Classification the origin (B cell or T cell) and maturity of the
-
leukemic cells (B-cell ALL and T-cell ALL)

Fever, night sweats, unexplained weight loss

o Fever in a patient with acute leukemia
must always be treated as a sign of
infection until proven otherwise!
Leukemia cutis (or myeloid sarcoma): nodular skin
Painless lymphadenopathy
lesions with a purple or gray-blue color (non-tender
Bone pain
Clinical cutaneous plaque)
Airway obstruction (stridor, difficulty
findings Gingival hyperplasia
breathing) due to mediastinal or thymic
Thrombocytopenia (e.g., bleeding, bruising,
infiltration (primarily in T-cell ALL)
petechiae) and recurrent infections
Meningeal leukemia (or leukemic meningitis)

changes, or other CNS symptoms

Testicular enlargement (rare finding)

In bone marrow or peripheral blood > 20%

myeloblasts
In bone marrow or peripheral blood >20% Some subtypes (especially M3, or APL) exhibit Auer
Diagnostics lymphoblasts rods
No Auer rods o Pink-red, rod-shaped granular cytoplasmic
inclusion bodies in malignant immature
myeloblasts or promyelocytes

Chemotherapy
o CNS prophylaxis (Intrathecal
chemotherapy with or without radiation)
Treatment is indicated Chemotherapy
Indications in ALL: Prevention of leukemic
meningitis in all patients at the time of
diagnosis
Chronic leukemia
Chronic lymphocytic leukemia Chronic myeloid leukemia

A type of myeloproliferative neoplasm involving

low-grade B-cell lymphoma with
Definitions hematopoietic stem cells that results in overexpression of
lymphocytic leukocytosis
cells of myeloid lineage, especially granulocytes.

Ionizing radiation
Etiology Risk factor: (Advanced age, Family history)
benzene

Stage (0): Isolated lymphocytosis

Stage (1): + Lymphadenopathy
Stage (2): + Hepatomegaly and/or
splenomegaly
Classification
Stage (3): + Anemia (Hb < 11 g/dL)
Stage (4): + Thrombocytopenia (<

Note: stage 3 and 4 are high risk

Chronic phase:
o Weight loss, fever, night sweats, fatigue
Remain asymptomatic for a long period
o Splenomegaly
Weight loss, fever, night sweats,
o Lymphadenopathy is not typical in CML.
fatigue (B symptoms)
Clinical
Painless lymphadenopathy
findings Blast crisis:
Repeated infections
o The terminal stage of CML.
Symptoms of anemia and
o Symptoms resemble those of acute leukemia.
thrombocytopenia
o Rapid progression of bone marrow
pancytopenia

CML can cause extreme leukocytosis (often >

100,000/mm3) and is frequently associated with
basophilia.
lymphocytosis with a high percentage
Leukocyte alkaline phosphatase (LAP): Low LAP is a
of small mature lymphocytes
typical finding and can help distinguish CML from other
Blood smear: smudge cells (Gumprecht
Diagnostics types of leukemia and leukemoid reactions
shadows)
Bone marrow aspiration and biopsies:
Bone marrow aspiration is not
predominantly granulocytosis
necessary to confirm the diagnosis
confirmation of the Philadelphia chromosome
confirmation of the BCR-ABL1 fusion gene

Symptomatic CLL or advanced stage:

Chemotherapy
Treatment Refractory CLL or early recurrence in Targeted therapy: tyrosine kinase inhibitors
fit, young patients: allogeneic stem cell
transplantation

Hyperviscosity syndrome
Autoimmune hemolytic anemia
Complication Immunosuppression with subsequent
infections
Richter transformation

Important note:
Lymphadenopathy is a typical finding in lymphoid malignancies such as CLL and helps to differentiate CLL from
CML!
Unlike AML, CML is not characterized by recurrent infections during early stages, since the granulocytes are still
fully functional
Hyper-Leukocytosis
accompanied by leukostasis

Leukostasis (Symptomatic hyperleukocytosis)

A medical emergency characterized by tissue hypoxia and hypercoagulability due to an excessive number of
immature leukocytes causing microvascular obstruction

Etiology
Most commonly occurs in Acute myeloid leukemia (AML) than in ALL (Acute lymphoblastic leukemia)

Clinical features
Lungs and the CNS are most commonly affected
o Hypoxemic respiratory failure, Dyspnea and tachypnea
o Confusion and focal neurological deficits
Fever is common
Leukostasis can also cause tumor lysis syndrome and DIC (a frequent complication of Acute promyelocytic
-

Treatment
Cytoreduction
o Induction chemotherapy: treatment of choice for curative intent
o Leukapheresis: A process in which white blood cells are separated from the rest of the blood.
o Hydroxyurea
Transfusion medicine
Sources: AMBOSS, The slides.

Objectives
Knowledge Cognitive Skills
1. - List blood components provided by blood banks and 1. Choose the most appropriate investigations to diagnose
indications of transfusion for the different products transfusion reaction (blood tests) based on the available
clinical data
2. Understand the process of blood donation and some 2. Interpret blood tests (CBC with differential, peripheral
common contraindications blood film, coagulation profile, fibrinogen, hemolytic work
up, Direct antiglobulin test DAT, blood cultures)
3. Understand compatibility of blood products and identify 3. Formulate and prioritize a differential diagnosis for the
universal donor blood groups different presentations of transfusion reactions (fever, SOB,
hemolysis)
4. Describe common transfusion reactions and outline their 4. Develop an evidence-based management plan for the
basic management common transfusion reactions
5. Identify the possible risks of blood transfusion 5. Demonstrate the appropriate skills for patient education
6. Recognize the presence of national and institutional
guidelines for blood transfusion and transfusion reactions

ABO blood types

Type Blood type O Blood type A Blood type B Blood type AB

Antigens on RBCs No antigens A antigen B antigen A and B antigens

Antibodies in Anti-A and anti-B antibodies Anti-B Anti-A No antibodies

plasma antibodies antibodies

Can receive RBCs O A, O B, O AB, A, B, O (universal RBC

from recipients)

O, A, B, AB (universal RBC A, AB B, AB AB
Can donate RBCs to
donors)

Can receive FFP O, A, B, AB (universal FFP A, AB B, AB AB

from recipients)

O A, O B, O AB, A, B, O (universal FFP

Can donate FFP to
donors)

Rh blood types
Type Rh-negative Rh-positive

Rh(D) antigen on RBCs Absent Present

Antibodies in plasma Anti-Rh antibodies can form after No anti-Rh antibodies

sensitization

Can receive RBCs from Rh negative (preferably) Rh positive, Rh negative

Can donate RBCs to Rh negative, Rh positive Rh positive

Important note: Individuals with blood type O can only receive RBCs from other blood type O donors. RBCs from
donors of any other type (e.g., A, B, or AB) can cause acute hemolytic transfusion reactions.
Important note:
Anti-Rh antibodies
o Usually only form in antigen-negative individuals after exposure to antigen-positive RBCs, e.g., transfusion,
fetomaternal hemorrhage
o Can lead to hemolytic disease of the fetus and newborn (HDFN) and/or delayed hemolytic transfusion
reactions (DHTR) in sensitized individuals
In Rh-negative women of childbearing age, exposure to Rh-positive RBCs (e.g., by transfusion or fetomaternal
hemorrhage) can trigger maternal Rh alloimmunization, which can cause HDFN in subsequent pregnancies. Rh-
negative donor blood is therefore preferred in these patients; however, Rh-positive blood is acceptable if an
emergency transfusion is required.
Fresh frozen plasma (FFP) transfusions do not need to be Rh-compatible as the risk of transfusion reactions
and/or subsequent alloimmunization is low.

Definition note (Hemolytic disease of the newborn)

A condition characterized by the destruction of fetal red blood cells (RBC) and anemia. Most frequently caused by
Rhesus (more severe) or ABO incompatibility (milder) between the mother and fetus, leading to immune-mediated
hemolysis in the fetus/neonate.
Transfusion safety measures
Blood products for transfusion can be allogeneic (i.e., from a donor) or autologous.
o Allogeneic donor blood is tested to determine blood type, screened for common infectious diseases, and
then leukoreduced.
Some blood donations undergo additional processing to further reduce the risk of complications in high-
risk groups.
o Blood for autologous transfusion typically undergoes minimal processing intraoperatively prior to
retransfusion (E.g., the addition of anticoagulant, filtering for debris and clots, saline washing).
Infection control
o Leukoreduction: filtration of leukocytes out of cellular blood products
Reduces the risk of nonhemolytic febrile transfusion reactions, HLA alloimmunization, and transmission
of CMV, HTLV-1/2, and EBV via leukocytes
Prolongs the lifespan of pRBC in storage
o Blood donation infection screening (Laboratory screening)
HIV, hepatitis B, hepatitis C, and HTLV
Despite the low risk of transmission of hepatitis B after routine screening, hepatitis B vaccination is
recommended for patients who require frequent transfusions.
Additional processing (patients with certain pre-existing conditions)
o Irradiation
Radiation exposure inactivates lymphocytes to reduce the risk of transfusion-associated graft-versus-
host disease (ta-GvHD).
o Washing
Replaces plasma in cellular blood products with an alternative solution to reduce the risk of an allergic
reaction (in patients with a history of IgA deficiency or severe allergic reaction to blood products).
Monitoring
o Check clinical status and vital signs for every unit transfused
o Monitor for signs of fluid overload, especially in patients requiring multiple transfusions.
o Observe inpatients for 24 hours after transfusion.
Pretransfusion testing
o Goal: Ensure compatibility between recipient and donor blood products and avoid hemolytic transfusion
reactions.
o Methods: hemagglutination (i.e., clumping of erythrocytes) induced by antibodies binding to RBC antigens
RBC: Blood typing, RBC antibody screen, and crossmatching are typically required.
FFP: Blood typing is typically required.
Overview
o Type & screen: determine the ABO and Rh group of the recipient
o Antibody screening: tests
blood cell antigens on screening red cells.
o A crossmatch is the final step to confirm that a RBC unit is compatible with the patient
Immediate spin crossmatch involves mixing of donor RBCs and recipient plasma
 Note: The indirect Coombs test is used to detect hemolytic anti-RBC IgG antibodies (against foreign RBC
antigens) present in a patient's serum. It is used to screen for maternal anti-D IgG antibodies (detection
of hemolytic disease of the newborn) and to crossmatch blood before transfusions.

Transfusion product
Whole blood
o Content: all blood components
o Indications
Planned surgery (autologous blood)
Autologous blood transfusion reduces the risk of transfusion reactions and is considered acceptable
by groups that would decline donor blood (e.g., Jehovah's witnesses).
Management of traumatic massive hemorrhage, as an alternative to fixed transfusion ratios
o Whole blood is rarely used, as most patients require just one blood component, e.g., pRBCs to treat anemia.
Fractionated blood components
o They are prepared by separating whole blood into its constituent elements and storing each under ideal
conditions.
Packed red blood cells (pRBC)
Platelet transfusion
Fresh frozen plasma (FFP)
Cryoprecipitate
Plasma derivatives

Definition Note (autologous blood): A term that usually describes cells or tissue components that are removed
from a patient and used for transfusion or transplant back to the same patient.

Type Packed red blood cells

RBCs
Content
Unit volume: 200 350 mL

Time 1 unit is transfused over 2 hours (maximum 4 hours)

Compatibility Must be ABO compatible

requirements Give Rh(D)-negative to recipients with Rh(D)-negative pRBCs if possible.

Hemorrhagic shock
Exchange transfusion: e.g., in severe sickle cell disease
Severe anemia (even if asymptomatic)
o
o H -existing cardiovascular disease (CHF) or if the patient is due to
Indications undergo cardiac or orthopedic surgery
Moderate anemia if there was:
o Symptoms of anemia
o Increased risk of complications, e.g., acute onset, significant comorbidities, older age
o Signs of hypoxia
o Planned surgery (if expected blood loss)

-carrying capacity of the blood (Leading to improved organ perfusion

Effect and tissue oxygenation)
1 unit of pRBCs increases Hb value by 1 g/dL (10g/L)

Complication Repeated transfusions can lead to iron overload.

Important note about this table:

In an emergency, if the patient's blood group is unknown, type O blood can be given. Uncrossmatched RBCs
(type-specific) may be used as soon as the patient's blood type is known, transitioning to fully crossmatched
blood when available.
 Give Rh(D)-negative pRBCs to women of childbearing age and patients with a history of previous transfusion or
pregnancy, as transfusion of Rh(D)-positive RBCs may trigger Rh sensitization or hemolysis in previously
sensitized patients.
Indications for RBC transfusion are not determined solely by Hb value, but rather by an assessment of the clinical
circumstances and the patient's overall condition.
Example: A patient with congestive heart failure requires a non-urgent RBC transfusion, the unit of RBCs should
be transfused over 4 hours.

Type Platelets

Platelets suspended in plasma

Provided as either:
o Single donor apheresis platelets (SDAP) unit: derived from 1 unit of whole blood from
Content a single donor
o Random donor pooled platelets (RDP) pack: derived from 4 6 units of whole blood
from various donors
Shelf-life of 5 days and stored at room temperature (20-24C)

Time 1 dose of platelets should be infused over 1-2 hours (Maximum infusion time is 4 hours)

Compatibility
The risks of incompatible platelet transfusion are lower than those of incompatible pRBCs.
requirements

Treatment of active bleeding in patients with any of the following:

o Platelets <50,000/mm3
o Qualitative platelet disorders
o Platelets < 100,000/mm3 PLUS brain injury or multiple trauma
Indications
Prevention of bleeding in any of the following situations:
o Severe thrombocytopenia (platelets < 10,000/mm3 )
o Patients with thrombocytopenia who are due to undergo invasive procedures (give
prophylactic platelet transfusions and is recommended when platelet count is
<10x10^9L)

1 unit of apheresis platelets or 1 pack of pooled platelets increases the platelet count by 20
Effect
60,000/mm3

Complication Multiple platelet transfusions may lead to platelet transfusion refractoriness.

Note about this table:

Patients with thrombocytopenia who are due to undergo invasive procedures
o Elective central venous catheter placement or bone marrow aspirate in patients with platelets <
20,000/mm3
o Neurosurgery in patients with platelets < 100,000/mm3
o Other invasive procedures in patients with platelets <50,000/mm3
In patients with fever (T>38.5) or coagulopathy (INR>1.5) the likelihood of bleeding is increased and prophylactic
platelet transfusion support may be indicated when the platelet count is <20x10^9/L
Non-immune causes of platelet transfusion refractoriness include sepsis, drugs, and splenic sequestration
Example: Patient with aplastic anemia (low platelet, low WBC and low Hb) with a platelet count of 15x10^9/L but
has no bruising or bleeding. Platelet count should be below 10x10^9/L to be transfused
o Same patient but he develops acute bowel perforation requiring abdominal surgery: give a minimum of
50x10^9/L platelet count to minimize risk of hemorrhage

Do not use platelet transfusions to treat severe thrombocytopenia due to ITP, TTP, HUS, Heparin-induced
thrombocytopenia (HIT) or catastrophic antiphospholipid antibody syndrome unless there is major bleeding.
 Type Fresh frozen plasma

Plasma, including all coagulation factors and plasma proteins

All cellular components are removed from the transfusion product.
Content
Unit volume: 200 300 mL
Usual dose of plasma is 10-15mL/kg (about 3 to 4 units of plasma)

Each unit is giver over 30 min -

Time
overload (maximum infusion time of 4 hours per unit)

Compatibility ABO compatibility must be considered.

requirements Rh(D) matching: not required

Management of coagulopathy in patients with multiple clotting factor deficiencies (e.g., due to
liver cirrhosis, DIC)
Indications Plasma exchange transfusion, e.g., in TTP
Immediate reversal of warfarin in patients with life-threatening bleeding or intracranial
hemorrhage

Effect Correction of both isolated and multiple coagulation factor deficiencies

INR 1.5 or less (including major or minor procedure/surgery)

Coagulopathy in the absence of bleeding or need for emergency surgery
when is FFP is not Elective reversal of warfarin where time allows for warfarin cessation and/or use of vitamin K
useful Reversal of other anticoagulants (e.g., heparin/LMWH, rivaroxaban and dabigatran) because
plasma has no effect in reversing or neutralizing heparins or thrombin inhibitors
Volume expansion or nutritional support

Type Cryoprecipitate

Clotting factors (fibrinogen, factor VIII, factor XIII), vWF, and fibronectin
Used for fibrinogen replacement
Content
The dose is 1 unit per 7-10kg body weight, however it is dispensed as a pool of 10 units

Time Infusion time is 15-30 minutes per dose (maximum infusion time 4 hours)

Compatibility ABO compatibility: preferred but not required

requirements Rh(D) matching: not required

Bleeding associated with fibrinogen deficiency (e.g., due to DIC, liver disease): typically performed
if serum fibrinogen is < 100 150 mg/dL (hypofibrinogenemia)
Indications
Alternative therapy for deficiencies in clotting factors, including vWF, factor VIII, and factor XIII
Treatment of uremic bleeding syndrome

1 unit of cryoprecipitate per 7 10 kg of the patient's body weight increases serum fibrinogen by 50
Effect
75 mg/dL.

Rarely, transfusion of large volumes of ABO-incompatible cryoprecipitate may lead to a mild

Complication
hemolytic transfusion reaction.

In conclusion for this table:

Cryoprecipitate is primarily used to treat bleeding associated with fibrinogen deficiency.
It is used for patients with hereditary disorders of hemostasis ONLY when specific factor concentrates are not
available (e.g., recombinant factor VIII)
Plasma derivatives (Additional)
This table below has been mentioned before in other lectures

Prothrombin complex
Type Single-factor concentrates Antithrombin III
concentrate (PCC)

Vitamin K-dependent
clotting factors: factors II, Antithrombin III, which is synthesized
VII, IX, and X specific clotting factors that have in the liver and inhibits coagulation
Content
Anticoagulants: protein C, been pooled from multiple donors factors IXa, Xa, XIa, and XIIa, and
protein S, antithrombin, thrombin
and/or heparin

Hereditary antithrombin III

specific clotting factor deficiencies
deficiency to optimize thrombosis
(e.g., factor VIII and factor IX are
prophylaxis with heparin
Vitamin K antagonist-associated used for the treatment of
Indications Patients on cardiopulmonary
major bleeding hemophilia A and hemophilia B) if
bypass who are experiencing
recombinant factors are not
heparin resistance
available
DIC

Effect increases the effects of heparin

Thrombotic complications
(e.g., VTE, myocardial
infarction) Recombinant factors are preferred
Heparin-induced if available, as they are associated
Adverse
thrombocytopenia (From with a lower risk of viral
effect
PCC preparations that transmission than single-factor
include heparin) concentrates.
Hypersensitivity reactions
(e.g., anaphylaxis)

Important note about Emergency transfusion

Unknown recipient blood type
o pRBCs: Uncrossmatched blood type O (universal RBC donor) pRBCs (Rhesus D negative if possible)
o FFP: Blood type AB (universal plasma donor) FFP
o Platelets: Ideally use blood type AB platelets (preferably Rh(D)-negative) but platelets of any blood type may
be used.
Known recipient blood type
o pRBCs: Uncrossmatched ABO and RhD-compatible pRBCs
o FFP: ABO-compatible FFP
o Platelets
ABO-compatible platelets are preferred but platelets of any blood type may be used.
Rh(D)-negative platelets are preferred for Rh(D)-negative recipients.

Conclusion in emergencies
Group O erythrocytes can be transfused to anyone
Group AB plasma and platelets can be transfused to anyone
Rh(D)-positive patients can safely receive either D-positive or D-negative blood, But Rh(D)-negative patients
must receive D-negative blood and platelets
Transfusion reactions
Transfusion reactions related to Fever
Type Background Clinical features Management
Stop transfusion until AHTR
has been ruled out.
Febrile nonhemolytic More common in children During or up to 6 hours
Use leukoreduced blood
transfusion reaction Over long periods of storage, after transfusion
products for prevention.
(FNHTR) WBCs can leak cytokines into Fever, chills, malaise,
Consider acetaminophen
- Greatest frequency - donor plasma. flushing, headache
(Paracetamol) for
symptoms.

Immediately stop
transfusion and notify the
blood bank.
Donor RBCs are destroyed by Rapid; during or up to 24
Perform Direct Coombs test
preformed recipient antibodies hours after transfusion
on recipient blood.
Acute hemolytic (typically due to ABO Fever, chills, nausea,
Repeat blood typing and
transfusion reaction incompatibility) flushing
crossmatching of the donor
(AHTR) Commonest cause of it is Signs of shock
blood.
errors in recipient Respiratory distress signs
Start immediate
identification Signs of hemolysis
hemodynamic support and
treat complications
(hyperkalemia, DIC)

Immediately stop the

transfusion.
Onset within 4 hours of
Start immediate
Bacterial contamination of blood transfusion
hemodynamic support
Transfusion-associated product (most common Fever, hypotension, rigor
Obtain blood cultures from
sepsis or contamination transfusion-transmitted infection and other signs of Systemic
both patient and remaining
from platelet transfusion) inflammatory response
blood product.
syndrome
Administer broad-spectrum
empiric antibiotic therapy

Pulmonary transfusion complications (Dyspnea)

Type Background Clinical features Management
Onset: Sudden; during or
Activation of primed granulocytes up to 6 hours after
Immediately stop
(Neutrophils) in recipient's lungs by transfusion
Transfusion-related transfusion
donor blood components leads to an Features resembling ARDS
acute lung injury Respiratory support: e.g.,
inflammatory cascade, culminating in Respiratory distress signs
(TRALI) lung-protective ventilation
lung injury and Noncardiogenic Signs of increased work of
Hemodynamic support.
pulmonary edema breathing
Fever, hypotension

Onset during or within 12

hours of transfusion Respiratory support: e.g.,
Transfusion-
Fluid overload underlying Signs of hypervolemia: oxygen therapy, mechanical
associated
cardiovascular or renal disease, and shortness of breath, S3 ventilation
circulatory overload
low body weight. gallop, jugular venous Consider diuretics to correct
(TACO)
distention, hypertension volume status.
(CHF)

Type I hypersensitivity reaction to Onset: Sudden; during or Immediately stop

donor plasma proteins (due to up to 3 hours after transfusion.
Anaphylactic
preformed recipient antibodies) transfusion Epinephrine IM
transfusion
recipients with Clinical features of Immediate hemodynamic
reaction
IGA deficiency who have antibodies to anaphylaxis (Pruritus, support
urticaria) Airway management
 TRALI TACO
Blood pressure Low-normal Normal-high
Body temperature Normal-elevated Normal
CXR No vascular congestion Vascular congestion
BNP Low (<250 pg/ml) High
PAOP Low-normal High
Ejection fraction Normal function Abnormal function
Response to diuretics Inconsistent Improved
Edema fluid Transudate Exudate

Cytopenia as a transfusion reaction

Type Background Clinical features Management

Onset: 5 10 days after

Delayed anamnestic response to platelet transfusion
Post-transfusion antigens leads to antibody-mediated Petechiae, purpura
IVIG therapy
purpura (PTP) destruction of both donor and recipient Diagnosis requires testing
platelets. the patient for platelet
specific antibodies

Fever, rash, and

Transfusion- most commonly occurs in gastrointestinal upset.
Rare complication and
associated graft- immunosuppressed patients. Laboratory studies show
is almost universally
versus-host disease Lymphocytes in the transfused blood pancytopenia and fatal.
(TA-GVHD) attack host tissues deranged liver
chemistries.

Definition Note: Anamnestic response is the rapid reappearance of antibodies and cellular immune activity
following exposure to a previously encountered antigen.

Other conditions for transfusion reaction

Type Background Clinical features Management

Onset: days or weeks

No acute therapy
after transfusion
Delayed anamnestic response to specific required (self-
Delayed hemolytic Most commonly
donor RBC antigens (e.g., Rh(D) antigen) limiting)
transfusion reaction asymptomatic
leads to extravascular hemolysis mediated Direct Coombs test
(DHTR) Features may include
by recipient antibodies. to prevent future
mild fever, jaundice,
reaction
signs of anemia

Iron overload (secondary

May occur with repeated blood transfusion, e.g., in thalassemia, sickle cell anemia
hemochromatosis)

Bloodborne viral, treponemal, and parasitic infections (e.g., HIV, hepatitis B, hepatitis C, West Nile virus, HTLV): uncommon

Conclusion
Suspect an acute transfusion reaction in any patient who develops a change in vital signs (e.g., fever, hypotension) or
any other new symptom during or within 24 hours of blood product transfusion.
Initial management steps for acute transfusion reactions to all patients
o Immediately discontinue the transfusion
o Do not restart blood component transfusion before a severe transfusion reaction has been ruled out.
Initial investigations for all patients
o Repeat patient and donor ABO typing and crossmatching
 Type Background Characteristic findings Management
Fever and chills
Flank and abdominal pain
Dyspnea Transfusion discontinuation
Acute hemolytic Results from ABO
Hypotension and tachycardia IV hydration
transfusion reaction incompatibility
Red plasma and urine Cardiovascular support
Free hemoglobin in the plasma
Positive DAT (Coombs test)
Unexplained drop in hemoglobin
Results from delayed concentration
emergence of an Elevated serum bilirubin and LDH No acute therapy required
Delayed hemolytic alloantibody that causes levels (self-limiting)
transfusion reaction rapid extravascular clearance Increased reticulocyte count Do direct Coombs test to
of transfused erythrocytes 2 Decreased haptoglobin prevent future reaction
to 10 days after transfusion concentration
Presence of new alloantibody
Stop transfusion until AHTR
Occurs during or after a
has been ruled out.
transfusion and it is caused During or up to 6 hours after
Use leukoreduced blood
Febrile non-hemolytic by donor leukocyte cytokines transfusion
products for prevention.
transfusion reaction or recipient alloantibodies Fever, chills, malaise, flushing,
Consider acetaminophen
directed against donor headache
(antipyretic) for symptoms.
leukocytes
Continue under observation
It is rare and severe reaction,
and it is causes by anti- During or within 6 hours of
Transfusion-related leukocytes antibodies transfusing erythrocytes, platelets Transfusion should be stopped
acute lung injury reacting with recipient or FFP Respiratory support provided
(TRALI) leukocytes and causing Hypoxemia and noncardiogenic (diuretics + Oxygen therapy)
leukocyte aggregation in the pulmonary edema
pulmonary capillary bed
Most common serious
complication
In patients with
Onset during or within 12 hours of
underlying heart or
Transfusion- transfusion
kidney disease but Same as cardiogenic pulmonary
associated circulatory Signs of hypervolemia: shortness of
should be considered in edema
overload (TACO) breath, S3 gallop, jugular venous
any patient with new
distention, hypertension (CHF)
respiratory symptoms
during or withing 12
hours of transfusion
Antihistamines and
Occurs when donor plasma Rash, hives glucocorticoids
Allergic transfusion
constituents react with a Wheezing Patient with IgA deficiency are
reaction
Mucosal edema at high risk because of the
presence anti-IgA antibodies
Rare but fatal
complication
Donor lymphocytes Fever, rash, and gastrointestinal
Transfusion-
engraft in an upset.
associated graft-
immunocompromised Laboratory studies show
versus-host disease
or HLA-similar recipient pancytopenia and deranged liver
(TA-GVHD)
and cause reactions that chemistries.
affect the bone marrow,
liver, skin and GI tract
Coagulation
Sources: AMBOSS, The slides, First aid.

Objectives
Knowledge Cognitive Skills
1. Identify the common anticoagulants 1. Choose the most appropriate investigations to monitor the
different anticoagulants effect (blood)
2. Understand their mechanism of action 2. Interpret blood tests (CBC, creatinine and coagulation profile)
3. Describe the basic pharmacology of different types of 3. Develop an evidence-based management plan for bleeding
anticoagulants (vitamin K antagonists, Direct Oral patients receiving anticoagulants
anticoagulants (DOACS), antithrombin agents)
4. Identify the side effects and the available reversing 4. Demonstrate the appropriate skills for patient education.
agent for each class
5. Describe heparin-induced thrombocytopenia (HIT) and
outline its management plan.

Review of basics
As mentioned before in this file, hemostasis is divided into primary
(platelet plug formation) and secondary which is:
The coagulation cascade, formed of 3 pathways
o Intrinsic pathway activated by damage to the vessel wall
o Extrinsic pathway activated by damage to the surrounding tissue
o Common pathway starts with activation of factor 10 through
intrinsic and extrinsic pathways, and leads to formation of fibrin
Note:

Coagulation Tests
Partial thromboplastin time (PT): measures the extrinsic pathway
Activated partial thromboplastin time (aPTT): measures the intrinsic pathway
If both PT and aPTT are abnormal, the defect is in the common pathway
Anti-Xa level: to measure the activity of heparin

PT APTT Fibrinogen Platelets Conditions

Normal hemostasis
Disorder of platelet
Normal Normal Normal Normal Factor 13 deficiency
Von Willebrand deficiency
LMWH and direct acting inhibitors
Factor 7 deficiency
Long Normal Normal Normal
Liver impairment and vitamin K deficiency
Normal Long Normal Normal Factor 8, 9, 11, 12 deficiency
Vitamin K deficiency
Long Long Normal or abnormal Normal
Anticoagulants (warfarin, direct acting, heparin)
Normal Normal Normal Low Thrombocytopenia
Massive transfusion
Long Long Normal or abnormal Low Liver disease
DIC

Indications of anticoagulants
Cardiac indications (e.g., atrial fibrillation, mechanical metallic heart valve, cardiac/vascular procedure)
Venous thromboembolism (VTE): DVT and PE
Prophylaxis for VTE
Heparin-Induced Thrombocytopenia (HIT)
Medications
Parenteral anticoagulants (IV anticoagulants) Oral anticoagulants
o Indirect anticoagulants (increase o Direct Oral Coagulation (DOACs)
antithrombin) Direct thrombin inhibition: Dabigatran,
Unfractionated heparin Argatroban
Low-molecular-weight-heparins (LMWHs) Direct factor Xa inhibition: ApiXAban,
Fondaparinux RivaroXAban
o Direct anticoagulants (inhibit thrombin) o Warfarin (vitamin K antagonist)
Argatroban

Overview
Medication Mechanism Indication Adverse effects Contraindications

Parenteral

Preferred for:
Inhibits thrombin by
Patients with high past or present heparin-
increasing activity of
Unfractionated risk of bleeding Heparin-Induced induced
antithrombin
Heparin (UFH) Given before Thrombocytopenia (HIC) thrombocytopenia and
It is also has weak
warfarin for renal active bleeding
factor Xa inhibition
failure patients

Low Molecular
Weight Heparin
Inhibits thrombin by Preferred for: Contraindicated in
(LMWH) Heparin-Induced
increasing activity of Cancer patients patients with Creatinine
Thrombocytopenia (HIC)
antithrombin and Pregnancy clearance (CrCl) <15
enoxaparin, more than UFH
inhibition of factor Xa Extreme weights mL/min
tinzaparin,
deltaparin

Contraindicated in
Used for prevention of Occasionally low platelet
Fondaparinux inhibition of factor Xa severe renal failure (CrCl
DVT and PE count
< 30 mL/min)

Indicated for heparin- history of

Direct thrombin
Argatroban induced Allergic reactions, fever hypersensitivity to
inhibitor
thrombocytopenia (HIC) argatroban

Oral

Preferred for:
Prosthetic heart
valves and valvular
Difficult to manage
heart disease Pregnancy
inhibits synthesis of Broad range of
Antiphospholipid teratogenic (can cross
Warfarin vitamin K-dependent interactions
syndrome the placenta, and impairs
clotting factors Not suited for acute
Thrombus in the development)
therapy of PE, DVT
heart
Moderate to severe
kidney injury

Limited clinical
Direct Oral experience
Anticoagulants Not recommended,
(DOACs) Commonly used for and partially
Thrombin and factor Xa prevention of stroke in contraindicated, in See when Warfarin is
Dabigatran, inhibition non-valvular Atrial patients with artificial preferred
Argatroban Fibrillation (NVAF) cardiac valves
Apixaban, Not suited for patients
Rivaroxaban with valvular atrial
fibrillation
General notes regarding anticoagulants
Generally, the most serious side effects to be considered with any anticoagulant is risk of bleeding
Expected laboratory changes
o Warfarin: increased PT/INR, it affects the extrinsic pathway
o Direct thrombin inhibitors; not routinely monitored
o Direct factor Xa inhibitors; not routinely monitored

Regarding warfarin
o Requires bridging with UFH
o Target INR 2-3 (in patients with metallic valve: target INR is 2.5-3.5)
o Management of elevated INR in patients receiving Warfarin:
INR 3.5-5: Skip one warfarin dose, monitor INR
INR 5-9: Skip 1-2 doses, monitor. Vitamin K may be used for urgent procedure
INR >9: Hold warfarin and give vitamin K, monitor the INR
Warfarin-associated major bleeding at any INR level:
Hold warfarin
Hospitalization may be needed
Prothrombin complex concentrate (PCC) is the first-line for rapid transfusion, preferred over Fresh
Frozen Plasma (FFP) as it has faster onset and less risks of allergy and infection

Note:

Heparin-Induced Thrombocytopenia (HIT)

antibody-mediated response to heparin (most commonly UFH) leading to thrombocytopenia and an increased risk of
thrombosis
Clinical events
Venous thrombosis (most common)
Arterial thrombosis
Skin lesions at heparin injection sites
Acute anaphylactoid reactions
Disseminated intravascular coagulation (DIC)

Diagnosis
Clinical: the patient will have thrombosis/ischemia
Pathological: thrombocytopenia and a positive serological assay for IgG antibodies

Treatment
Discontinue ALL heparin immediately
Initiate non heparin anticoagulation
o DOACs are the first line
o Warfarin is the second line
Monitor carefully for thrombosis
Avoid prophylactic platelet transfusions
Document HIT in medical records
Laboratory evaluation
Monitor platelet counts recovery
Additional Topics in hematology
Hypercoagulable states (Thrombophilia)
Definition
Thromboembolism: The formation and/or migration of blood clots in different locations of the venous or arterial
vasculature that can occlude or impair the pulmonary or systemic circulation.
o Venous thromboembolism (VTE)
Examples include deep venous thrombosis, pulmonary embolism
o Arterial thromboembolism
Usually, an acute event that results in ischemic tissue damage (e.g., stroke, acute mesenteric ischemia,
acute limb ischemia, acute coronary syndrome, pulmonary infarction)
Etiology
Risk factors for thromboembolic disease
o Venous thrombosis
trauma, fractures, major orthopedic surgery, oncological surgery, immobilization combined with other
risk factors
exogenous estrogen (e.g., OCPs, HRT); pregnancy
o Arterial thrombosis
Smoking
Obesity

Hereditary causes of hypercoagulability Acquired causes of

hypercoagulability

Factor V Leiden (autosomal dominant inheritance): most

common genetic cause of hypercoagulability in white
populations
Predisposing to venous Protein C deficiency Malignancy
thrombosis Antithrombin III deficiency Nephrotic syndrome
Prothrombin G20210A mutation
Hyperhomocysteinemia
Sickle cell anemia

Antiphospholipid
syndrome
Predisposing to both venous Heparin-induced
and arterial thrombosis
Protein S deficiency
thrombocytopenia
Systemic lupus
erythematosus

Clinical features
Clinical features suggestive of underlying thrombophilia
o VTE characteristics
Onset at age < 50 years of either of the following:
Unprovoked VTE
VTE associated with only weak risk factors
o Unusual thrombus localization
o Strong family history of VTE
o Recurrent VTE or multiple VTE
o Arterial thromboembolism (e.g., stroke) in a young patient with no cardiovascular risk factors
Clinical features of thromboembolism
o VTE (most common)
o Arterial thromboembolism
Ischemic stroke
Acute coronary syndrome
Others: e.g., the 6 P's of acute limb ischemia, clinical features of intestinal ischemia
Diagnostics

Hereditary thrombophilias
o Activated protein C resistance assay
o Prothrombin G20210A mutation testing
o Activity assays for protein C, protein S, antithrombin
Acquired thrombophilias
o antiphospholipid antibody panel (lupus anticoagulants, anticardiolipin antibodies)
Screening for occult malignancy
o Indications: unprovoked VTE (especially in patients aged >50 years), recurrent VTE

Treatment
Venous thromboembolism
o anticoagulant administration
o Consider an inferior vena cava filter if anticoagulant therapy is contraindicated
Acute management of specific thrombophilias
o Heparin-induced thrombocytopenia type II
Heparin is contraindicated and argatroban or lepirudin should be prescribed instead
o Antiphospholipid syndrome
Anticoagulation regimens: lifelong anticoagulation usually required
VTE: Vitamin K antagonists (e.g., warfarin) with heparin bridging
Prevention
Standard VTE prophylaxis is indicated in select circumstances regardless of thrombophilia status (e.g., postoperative
status, prolonged immobilization or hospitalization, active malignancy)

Management of asymptomatic thrombophilia

Obesity: Recommend weight loss.
Tobacco use: Encourage smoking cessation.
Avoid estrogens (e.g., OCPs)
o Avoid in patients who are carriers of Factor V Leiden.
High-risk situations: Primary prophylaxis (compression stockings, chemical prophylaxis with an LMWH or direct
oral anticoagulant) may be appropriate.
Surgery: Consider pneumatic stockings, early physiotherapy, and hydration in addition to the above measures.

Antiphospholipid syndrome
An autoimmune disease that increases the risk of thrombosis as a result of procoagulatory antibodies. The condition
may be idiopathic or acquired secondary to an underlying disease, such as systemic lupus erythematosus (most
common cause of secondary APS).

Pathophysiology
Formation of procoagulatory antiphospholipid antibodies
o Antibodies activate platelets and vascular endothelium

Clinical features
Recurring thrombotic events that may affect any organ
Venous
o Deep vein thrombosis
o Pulmonary embolism
o Livedo reticularis
o Ulceration
Arterial
o Stroke, transient ischemic attacks
o Occlusion of organ arteries (e.g., myocardial infarction)
o Occlusion of distal extremity arteries (ischemia and gangrene)
Capillaries: splinter hemorrhages
Pregnancy-related: recurrent miscarriages and premature births
Diagnostics
Serology: for antiphospholipid antibodies
o Lupus anticoagulant (LA): leads to a prolonged aPTT
Blood tests
o Thrombocytopenia
o Hemolysis, leukocytopenia

Treatment
Systemic anticoagulation
Acute management
o SC low molecular weight heparin (LMWH) or IV unfractionated heparin
Secondary prophylaxis
o Low risk: low-dose aspirin
o High risk and no desire to become pregnant: long-term treatment with oral warfarin
o Wish to have children: LMWH PLUS aspirin (prevention of miscarriage)